Pharmacokinetic Properties of Azithromycin in Pregnancy

Salman, Sam; Rogerson, Stephen J.; Kose, Kay; Griffin, Susan; Gomorai, Servina; Baiwog, Francesca; Winmai, Josephine; Kandai, Josin; Karunajeewa, Harin; O’Halloran, Sean; Siba, Peter; Ilett, Kenneth F.; Müeller, Ivo; Davis, Timothy M. E.

doi:10.1128/aac.00771-09

Cited by 43 publications

(54 citation statements)

References 42 publications

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“…As such, a number of investigators have assessed the pharmacokinetics of AZ in gravid (29,41) and nongravid (34,(42)(43)(44) animal models, as well as in humans (14,45,46). Although the MP pharmacokinetics of AZ in humans at term (45) and in the late second trimester (46) are well described, there remains a lack of data describing the fetal uptake of AZ in the second trimester of pregnancy.…”

Section: Discussionmentioning

confidence: 99%

Maternal Intravenous Administration of Azithromycin Results in Significant Fetal Uptake in a Sheep Model of Second Trimester Pregnancy

Kemp

Miura

Payne

et al. 2014

Antimicrob Agents Chemother

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g Treatment of intrauterine infection is likely key to preventing a significant proportion of preterm deliveries before 32 weeks of gestation. Azithromycin (AZ) may be an effective antimicrobial in pregnancy; however, few gestation age-approriate data are available to inform the design of AZ-based treatment regimens in early pregnancy. We aimed to determine whether a single intra-amniotic AZ dose or repeated maternal intravenous (i.v.) AZ doses would safely yield therapeutic levels of AZ in an 80-daygestation (term is 150 days) ovine fetus. Fifty sheep carrying single pregnancies at 80 days gestation were randomized to receive either: (i) a single intra-amniotic AZ administration or (ii) maternal intravenous AZ administration every 12 h. Amniotic fluid, maternal plasma, and fetal AZ concentrations were determined over a 5-day treatment regimen. Markers of liver injury and amniotic fluid inflammation were measured to assess fetal injury in response to drug exposure. A single intra-amniotic administration yielded significant AZ accumulation in the amniotic fluid and fetal lung. In contrast, repeated maternal intravenous administrations achieved high levels of AZ accumulation in the fetal lung and liver and a statistically significant increase in the fetal plasma drug concentration at 120 h. There was no evidence of fetal injury in response to drug exposure. These data suggest that (i) repeated maternal i.v. AZ dosing yields substantial fetal tissue uptake, although fetal plasma drug levels remain low; (ii) transfer of AZ from the amniotic fluid is less than transplacental transfer; and (iii) exposure to high concentrations of AZ did not elicit overt changes in fetal white blood cell counts, amniotic fluid monocyte chemoattractant protein 1 concentrations, or hepatotoxicity, all consistent with an absence of fetal injury.

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Section: Discussionmentioning

confidence: 99%

Maternal Intravenous Administration of Azithromycin Results in Significant Fetal Uptake in a Sheep Model of Second Trimester Pregnancy

Kemp

Miura

Payne

et al. 2014

Antimicrob Agents Chemother

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“…Consequently, a fixed value of 0.8 h Ϫ1 was selected based on the median value from the pilot study and those reported in the literature (9,36,49). The insensitivity of the parameter estimates to this fixed value was verified by varying the k a between 0.2 h Ϫ1 and 8 h Ϫ1 .…”

Section: Resultsmentioning

confidence: 99%

“…An interpretation of data from two studies which have examined azithromycin pharmacokinetics in pregnancy is confounded by their conflicting results and unique populations (46,49). Women undergoing caesarean section were evaluated in one study (46), and women in Papua New Guinea receiving antimalarial treatment were evaluated in the other (49). Intrinsic or environmental differences between these subjects and pregnant women receiving azithromycin for community-acquired infections in the United States hinder the generalization of their findings.…”

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confidence: 99%

“…Limited data are available regarding the influence of pregnancy on azithromycin pharmacokinetics. An interpretation of data from two studies which have examined azithromycin pharmacokinetics in pregnancy is confounded by their conflicting results and unique populations (46,49). Women undergoing caesarean section were evaluated in one study (46), and women in Papua New Guinea receiving antimalarial treatment were evaluated in the other (49).…”

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confidence: 99%

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Influence of Body Weight, Ethnicity, Oral Contraceptives, and Pregnancy on the Pharmacokinetics of Azithromycin in Women of Childbearing Age

Fischer

Sarto

Habibi

et al. 2012

Antimicrob Agents Chemother

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Women of childbearing age commonly receive azithromycin for the treatment of community-acquired infections, including during pregnancy. This study determined azithromycin pharmacokinetics in pregnant and nonpregnant women and identified covariates contributing to pharmacokinetic variability. Plasma samples were collected by using a sparse-sampling strategy from pregnant women at a gestational age of 12 to 40 weeks and from nonpregnant women of childbearing age receiving oral azithromycin for the treatment of an infection. Pharmacokinetic data from extensive sampling conducted on 12 healthy women were also included. Plasma samples were assayed for azithromycin by high-performance liquid chromatography. Population data were analyzed by nonlinear mixed-effects modeling. The population analysis included 53 pregnant and 25 nonpregnant women. A three-compartment model with first-order absorption and a lag time provided the best fit of the data. Lean body weight, pregnancy, ethnicity, and the coadministration of oral contraceptives were covariates identified as significantly influencing the oral clearance of azithromycin and, except for oral contraceptive use, intercompartmental clearance between the central and second peripheral compartments. No other covariate relationships were identified. Compared to nonpregnant women not receiving oral contraceptives, a 21% to 42% higher dose-adjusted azithromycin area under the plasma concentration-time curve (AUC) occurred in non-African American women who were pregnant or receiving oral contraceptives. Conversely, azithromycin AUCs were similar between pregnant African American women and nonpregnant women not receiving oral contraceptives. Although higher levels of maternal and fetal azithromycin exposure suggest that lower doses be administered to non-African American women during pregnancy, the consideration of azithromycin pharmacodynamics during pregnancy should guide any dose adjustments. Drug therapy in pregnant women must take into account the physiological changes accompanying pregnancy. These physiological changes can impact drug disposition by altering plasma protein binding, hepatic clearance, and renal excretion (6, 24). Depending on the type and extent of any alterations, an adjustment of the dose may be needed to ensure that the desired outcome is achieved and that the mother or fetus is not exposed to excess drug. For agents cleared by drug-metabolizing enzymes or transport proteins, an insufficient understanding of how pregnancy affects the activities of these pathways often hampers the devising of appropriate dosing strategies.Azithromycin is among the drugs most commonly prescribed to pregnant women (7). Its frequent use in pregnancy reflects its established safety and efficacy in nonpregnant women and men for the outpatient treatment of respiratory (23,39,44), skin (30), and gynecological (45) infections as well as the lack of an association between the maternal administration of azithromycin and an increased occurrence of major congenital malformations (14,5...

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“…Azithromycin (AZ) is a broad-spectrum macrolide (azalide) antibiotic with favorable antimalarial properties and a good safety profile in pregnancy (8,9). IPTp with SPAZ prevented LBW and preterm delivery in two clinical trials (10,11), and confounding may in part explain the observation of no effect in the third (6,12); this warrants its further evaluation as a potential alternative to SP-IPTp.…”

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confidence: 99%

Impact of Intermittent Preventive Treatment in Pregnancy with Azithromycin-Containing Regimens on Maternal Nasopharyngeal Carriage and Antibiotic Sensitivity of Streptococcus pneumoniae, Haemophilus influenzae, and Staphylococcus aureus: a Cross-Sectional Survey at Delivery

et al. 2015

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Intermittent preventive treatment in pregnancy (IPTp) with sulfadoxine-pyrimethamine (SP) can prevent low birth weight (LBW; Ͻ2,500 g) and reduces infant morbidity and mortality in resource-limited countries (1, 2). However, high-level resistance of Plasmodium falciparum to SP, recently observed in East Africa, may render IPTp-SP clinically inefficacious (3-5). The development and evaluation of new IPTp regimens are therefore of utmost importance (6, 7).Azithromycin (AZ) is a broad-spectrum macrolide (azalide) antibiotic with favorable antimalarial properties and a good safety profile in pregnancy (8, 9). IPTp with SPAZ prevented LBW and preterm delivery in two clinical trials (10, 11), and confounding may in part explain the observation of no effect in the third (6, 12); this warrants its further evaluation as a potential alternative to SP-IPTp.An integral part of such evaluation is to screen for adverse consequences, including the selection of drug-resistant Streptococcus pneumoniae (13), a principal cause of meningitis and respiratory infections in infants (14). Mass administration (MDA) of AZ to children has been associated with increased nasopharyngeal carriage of macrolide-resistant pneumococci, particularly when MDA was given at 6-to 12-monthly intervals (15)(16)(17)(18)(19)(20). However, this is not a unanimous finding (21) and may in part depend on the prevalence of resistant isolates at baseline (15-18). Longitudinal studies of carriage and resistance patterns indicate that in the event of MDA-driven temporary expansion of macrolide-resistant isolates, a decrease in their prevalence tends to occur 12 to 24 months after the most recent treatment (19,20). Citation Unger HW, Aho C, Ome-Kaius M, Wangnapi RA, Umbers AJ, Jack W, Lafana A, Michael A, Hanieh S, Siba P, Mueller I, Greenhill AR, Rogerson SJ. 2015. Impact of intermittent preventive treatment in pregnancy with azithromycincontaining regimens on maternal nasopharyngeal carriage and antibiotic sensitivity of Streptococcus pneumoniae, Haemophilus influenzae, and Staphylococcus aureus: a cross-sectional survey at delivery.

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Pharmacokinetic Properties of Azithromycin in Pregnancy

Cited by 43 publications

References 42 publications

Maternal Intravenous Administration of Azithromycin Results in Significant Fetal Uptake in a Sheep Model of Second Trimester Pregnancy

Maternal Intravenous Administration of Azithromycin Results in Significant Fetal Uptake in a Sheep Model of Second Trimester Pregnancy

Influence of Body Weight, Ethnicity, Oral Contraceptives, and Pregnancy on the Pharmacokinetics of Azithromycin in Women of Childbearing Age

Impact of Intermittent Preventive Treatment in Pregnancy with Azithromycin-Containing Regimens on Maternal Nasopharyngeal Carriage and Antibiotic Sensitivity of Streptococcus pneumoniae, Haemophilus influenzae, and Staphylococcus aureus: a Cross-Sectional Survey at Delivery

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