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Pharmacokinetics, safety, and biologic effects of azithromycin in extremely preterm infants at risk for ureaplasma colonization and bronchopulmonary dysplasia.

ABSTRACT: Ureaplasma spp. respiratory tract colonization is a significant risk factor for bronchopulmonary dysplasia (BPD), a chronic lung disorder in preterm infants. As an initial step preparatory to future clinical trials to evaluate the clinical efficacy of azithromycin to prevent BPD, the authors characterized the pharmacokinetics, safety, and biological effects of a single intravenous dose of azithromycin (10 mg/kg) in preterm neonates (n = 12) 24 to 28 weeks gestation at risk for Ureaplasma infection and BPD. A 2-compartment structural model with the clearance and volume of peripheral compartment (V2) allometrically scaled on body weight (WT) best described the pharmacokinetics of azithromycin in preterm neonates. The estimated parameters were clearance [0.18 L/h × WT(kg)(0.75)], intercompartmental clearance [1.0 L/h], volume of distribution of central compartment [0.93 L], and V2 [14.2 L × WT(kg)]. There were no serious adverse events attributed to azithromycin. A single dose of azithromycin did not suppress inflammatory cytokines or myeloperoxidase activity in tracheal aspirates. These results demonstrated the safety of azithromycin and developed a pharmacokinetic model that is useful for future simulation-based clinical trials for eradicating Ureaplasma and preventing BPD in preterm neonates.

SUBMITTER: Hassan HE

PROVIDER: S-EPMC4240745 | biostudies-literature | 2011 Sep

REPOSITORIES: biostudies-literature

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Pharmacokinetics, safety, and biologic effects of azithromycin in extremely preterm infants at risk for ureaplasma colonization and bronchopulmonary dysplasia.

Hassan Hazem E HE Othman Ahmed A AA Eddington Natalie D ND Duffy Lynn L Xiao Li L Waites Ken B KB Kaufman David A DA Fairchild Karen D KD Terrin Michael L ML Viscardi Rose M RM

Journal of clinical pharmacology 20101123 9

Ureaplasma spp. respiratory tract colonization is a significant risk factor for bronchopulmonary dysplasia (BPD), a chronic lung disorder in preterm infants. As an initial step preparatory to future clinical trials to evaluate the clinical efficacy of azithromycin to prevent BPD, the authors characterized the pharmacokinetics, safety, and biological effects of a single intravenous dose of azithromycin (10 mg/kg) in preterm neonates (n = 12) 24 to 28 weeks gestation at risk for Ureaplasma infecti ...[more]

PMID: 21098694

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Project description:Background: Infants born extremely preterm are at high risk of developing bronchopulmonary dysplasia (BPD). This study aimed to assess the incremental health care burden of BPD and associated comorbidities among extremely preterm infants in the United States. Methods: Health service claims in the Premier Perspective database were retrospectively analyzed for infants born at ?28 weeks gestation who were admitted to neonatal intensive care during birth hospitalization and survived to a postmenstrual age of ?36 weeks. Gestational age (GA) at birth and BPD status of infants was determined based on International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes recorded in the database. Results: Of the 12,017 infants included, 4,904 (40.8%) had BPD. BPD increased with decreasing GA: 67.4% of infants born at <24 weeks GA had BPD vs. 28.7% of those born at 27-28 weeks. Infants with BPD had significantly longer hospital stays following birth than those without (mean [standard deviation (SD)] 102 [34] vs. 83 [24] days, respectively, P < 0.001), and incurred higher total charges (mean [SD] $799,499 [$535,528] vs. $588,949 [$377,137], respectively, P < 0.001). Mean total charges incurred during index hospitalization decreased as GA at birth increased, with GA having a bigger effect than presence or absence of BPD. During their first year, infants with BPD had a higher in-hospital late mortality rate than those without (1.9 vs. 0.6%), and were more likely to have two or more hospital encounters following birth hospitalization (58.0 vs. 48.2%). Among infants who had two or more encounters after discharge, those with BPD experienced a higher percentage of pulmonary symptoms than those without (46.3 vs. 38.9%). Comparison with infants who did not have BPD, retinopathy of prematurity, or intraventricular hemorrhage showed that BPD is the main complication contributing to increased length of stay, costs, in-hospital mortality, and additional health care encounters. Conclusion: BPD is a key contributor to the large health care burden associated with extremely preterm birth. However, GA at birth has a bigger effect on health care costs for extremely preterm infants than the presence of BPD.

Project description:The study objectives were to refine the population pharmacokinetics (PK) model, determine microbial clearance, and assess short-term pulmonary outcomes of multiple-dose azithromycin treatment in preterm infants at risk for Ureaplasma respiratory colonization. Fifteen subjects (7 of whom were Ureaplasma positive) received intravenous azithromycin at 20 mg/kg of body weight every 24 h for 3 doses. Azithromycin concentrations were determined in plasma samples obtained up to 168 h post-first dose by using a validated liquid chromatography-tandem mass spectrometry method. Respiratory samples were obtained predose and at three time points post-last dose for Ureaplasma culture, PCR, antibiotic susceptibility testing, and cytokine concentration determinations. Pharmacokinetic data from these 15 subjects as well as 25 additional subjects (who received either a single 10-mg/kg dose [n = 12] or a single 20-mg/kg dose [n = 13]) were analyzed by using a nonlinear mixed-effect population modeling (NONMEM) approach. Pulmonary outcomes were assessed at 36 weeks post-menstrual age and 6 months adjusted age. A 2-compartment model with all PK parameters allometrically scaled on body weight best described the azithromycin pharmacokinetics in preterm neonates. The population pharmacokinetics parameter estimates for clearance, central volume of distribution, intercompartmental clearance, and peripheral volume of distribution were 0.15 liters/h · kg(0.75), 1.88 liters · kg, 1.79 liters/h · kg(0.75), and 13 liters · kg, respectively. The estimated area under the concentration-time curve over 24 h (AUC24)/MIC90 value was ∼ 4 h. All posttreatment cultures were negative, and there were no drug-related adverse events. One Ureaplasma-positive infant died at 4 months of age, but no survivors were hospitalized for respiratory etiologies during the first 6 months (adjusted age). Thus, a 3-day course of 20 mg/kg/day intravenous azithromycin shows preliminary efficacy in eradicating Ureaplasma spp. from the preterm respiratory tract.

Project description:BackgroundTo assess the potential impact of azithromycin treatment in the first week following birth on 2-year outcomes in preterm infants with and without Ureaplasma respiratory colonization who participated in a double-blind, placebo-controlled randomized controlled trial.MethodsRespiratory morbidity was assessed at NICU discharge and at 6, 12, and 22-26 months corrected age using pulmonary questionnaires. Comprehensive neurodevelopmental assessments were completed between 22 and 26 months corrected age. The primary and secondary composite outcomes were death or severe respiratory morbidity and death or moderate-severe neurodevelopmental impairment, respectively, at 22-26 months corrected age.ResultsOne hundred and twenty-one randomized participants (azithromycin, N = 60; placebo, N = 61) were included in the intent-to-treat analysis. There were no significant differences in death or serious respiratory morbidity (34.8 vs 30.4%, p = 0.67) or death or moderate-severe neurodevelopmental impairment (47 vs 33%, p = 0.11) between the azithromycin and placebo groups. Among all trial participants, tracheal aspirate Ureaplasma-positive infants experienced a higher frequency of death or serious respiratory morbidity at 22-26 months corrected age (58%) than tracheal aspirate Ureaplasma-negative infants (34%) or non-intubated infants (21%) (p = 0.028).ConclusionsWe did not observe strong evidence of a difference in long-term pulmonary and neurodevelopment outcomes in preterm infants treated with azithromycin in the first week of life compared to placebo.ImpactNo strong evidence of a difference in long-term pulmonary and neurodevelopment outcomes was identified at 22-26 months corrected age in infants treated with azithromycin in the first week of life compared to placebo. The RCT is the first study of 2-year pulmonary and neurodevelopmental outcomes of azithromycin treatment in ELGANs. Provides evidence that ELGANs with lower respiratory tract Ureaplasma have the most frequent serious respiratory morbidity in the first 2 years of life, suggesting that a Phase III trial of azithromycin to prevent BPD targeting this population is warranted.

Dataset Information

Pharmacokinetics, safety, and biologic effects of azithromycin in extremely preterm infants at risk for ureaplasma colonization and bronchopulmonary dysplasia.

Publications

Pharmacokinetics, safety, and biologic effects of azithromycin in extremely preterm infants at risk for ureaplasma colonization and bronchopulmonary dysplasia.

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