Meta-analyses of clinical studies over the past 30 years have confirmed Ureaplasma respiratory colonization as an independent risk factor for bronchopulmonary dysplasia (BPD). This application addresses the fundamental problem that there is currently insufficient data concerning the benefit/risk ratio of antibiotic therapy to recommend treatment guidelines to prevent BPD and long-term adverse pulmonary outcomes in preterm infants at-risk or with confirmed Ureaplasma infection. Our long- term objective is to develop therapies to eradicate Ureaplasma from the respiratory tract of preterm infants and prevent or ameliorate Ureaplasma-mediated lung injury. The azalide antibiotic azithromcyin (AZM) has antimicrobial and immunomodulatory properties that make it an ideal therapeutic candidate to prevent Ureaplasma-mediated lung injury. We conducted PK/PD studies characterizing the population PK, safety, tolerability, and biologic effects of a single dose of 10 and 20 mg/kg IV AZM and multiple dose 20 mg/kg x 3d in 24-28 wk gestation neonates who are at highest risk for Ureaplasma respiratory tract colonization and BPD. A 2-compartment model with all parameters allometrically scaled on body weight best described the PK of AZM in preterm neonates. Compared to the single dose groups, the 20 mg/kg multi-dose effectively eradicated Ureaplasma in all subjects who were colonized pre-dose. The multi-dose regimen appeared safe, with no deaths or serious adverse events attributed to the drug. Our objectives in this application are to determine the safety and microbiological efficacy of a short course of IV AZM to eradicate respiratory tract Ureaplasma infection and its' potential to improve short-term (BPD) and long-term pulmonary and neurodevelopmental outcomes in preterm neonates. The central hypothesis is that AZM therapy will reduce pulmonary morbidity in Ureaplasma-infected preterm infants by accelerating pathogen clearance and/or down-regulating the pulmonary inflammatory response. We have completed 80% planned enrollment in the current multicenter, randomized, double-blind, placebo-controlled Phase IIb clinical trial of 20 mg/kg x3d IV AZM.
The specific aims of this renewal application will extend outcomes up to 24 months adjusted age and will address the next steps preparatory to Phase III safety and efficacy trials of AZM in the preterm population.
The specific aims of this proposal are: 1) to determine the safety and microbiological efficacy of IV AZM to eradicate respiratory tract Ureaplasma infection in preterm neonates; 2) to analyze the potential of AZM to reduce BPD and improve long-term pulmonary outcomes; and 3) to assess the impact of AZM on the risk for neurodevelopmental impairment at 22-26 months adjusted age. The proposed research is significant because it will lead directly to decisions concerning future Phase III safety and efficacy trials of AZM in the preterm population and to evidence-based recommendations concerning the clinical evaluation and management of perinatally-acquired Ureaplasma respiratory colonization in the preterm population.
/RELEVANCE: The proposed research is relevant to public health because the proposed well-designed studies will establish the safety and microbiologic efficacy of azithromycin to eradicate perinatally-acquired Ureaplasma respiratory colonization, and the demonstrate the potential of this therapy to improve pulmonary and neurodevelopmental outcomes of infants born extremely preterm. Thus, the proposed research is relevant to the NICHD mission to ensure that all children have the chance to achieve their full potential for healthy and productive lives, free from disease or disability and supports the goal of the Better Pharmaceuticals fro Children Act (BPCA) Program to improve pediatric therapeutics through preclinical and clinical drug trials that lead to drug labeling changes.
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