zithromax and Bronchopulmonary-Dysplasia

Azithromycin has anti-Ureaplasma and anti-inflammatory properties that might help reduce lung injury in preterm infants.. To test the efficacy and safety of prophylactic or therapeutic azithromycin in preventing bronchopulmonary dysplasia (BPD) in preterm infants with unknown or proven Ureaplasma status.. We searched PubMed, Web of Science, and Cochrane Library until 13 September 2020. Two authors independently assessed the eligibility, risk of bias, and extracted the data. We performed a random-effects model meta-analysis to yield pooled relative risk (RR) or mean difference (MD) with 95% confidence interval (CI). We used the Cochrane GRADE methodology for summarizing the results.. We included five randomized clinical trials. The meta-analysis revealed no significant differences in BPD (RR, 0.92; 95% CI, 0.71, 1.19; low-quality evidence), death (RR, 0.75; 95% CI, 0.52, 1.10; low-quality evidence), and BPD or death (RR, 0.90; 95% CI, 0.74, 1.10; low-quality evidence). However, a significantly lower BPD or death (RR, 0.83; 95% CI, 0.70, 0.99) and a trend toward lower BPD (RR, 0.83; 95% CI, 0.66, 1.03) with azithromycin therapy was noted in Ureoplasma positive neonates. No differences in secondary outcomes were noted, except for significantly lower supplemental oxygen days with azithromycin (MD, -6.06; 95% CI, -7.40, -4.72; moderate-quality evidence). The test for subgroup differences between short (<7 days) and long (>7 days) course of azithromycin were nonsignificant for all the outcomes.. Low-quality evidence suggests azithromycin therapy reduces BPD or death in preterm infants with positive Ureoplasma, but not in all preterm infants.

Topics: Anti-Inflammatory Agents; Azithromycin; Bronchopulmonary Dysplasia; Humans; Infant; Infant, Newborn; Infant, Premature

Bronchopulmonary dysplasia (BPD) is the most common chronic complication of extreme preterm birth. The authors applied the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology to pharmacologic therapies found to prevent BPD. Caffeine and vitamin A are the only medications shown in high-quality studies to prevent BPD without the risk of clinically important adverse effects. Dexamethasone is effective for the prevention of BPD; but for many infants, the increased risks of hypertrophic cardiomyopathy, gastrointestinal perforation, and cerebral palsy outweigh this benefit. Several medications are currently under investigation for the prevention of BPD, but few are novel agents.

Topics: Anti-Bacterial Agents; Azithromycin; Bronchopulmonary Dysplasia; Caffeine; Cardiomyopathy, Hypertrophic; Central Nervous System Stimulants; Cerebral Palsy; Dexamethasone; Evidence-Based Medicine; Glucocorticoids; Humans; Infant, Newborn; Infant, Premature; Intestinal Perforation; Primary Prevention; Risk Assessment; Risk Factors; Vitamin A; Vitamins

To identify the use and adverse drug reactions associated with azithromycin in neonates.. Databases MEDLINE (1948-August 2015), EMBASE (1980-August 2015) and Pubmed (August 2015) were searched for studies on azithromycin in neonates.. All studies involving neonates (<28 days old) who have received at least a single dose of azithromycin for which safety was evaluated.. The primary outcome was adverse event (AE) associated with use of azithromycin. Use of azithromycin in neonates was the secondary outcome.. A total of 11 articles involving 473 neonates were identified. 371 AEs were reported. Adverse events were mainly respiratory (358/1000 neonate), neurological (273/1000 neonates) and gastrointestinal (196/1000 neonates) in origin. Azithromycin significantly reduced the risk of bronchopulmonary dysplasia (BPD) in extremely premature neonates (RR=0.83, 95% CI 0.71 to 0.98, p=0.02). There was no significant difference in the incidence of elevated liver enzymes between the azithromycin and placebo group (p=0.76). There were four cases of infantile hypertrophic pyloric stenosis (IHPS).. Azithromycin significantly reduces the risk of BPD in preterm neonates. The relationship between azithromycin and IHPS requires further investigation.

Topics: Anti-Bacterial Agents; Azithromycin; Bronchopulmonary Dysplasia; Humans; Infant, Extremely Premature; Infant, Newborn; Risk Factors

Ureaplasma spp. infection has been associated with bronchopulmonary dysplasia (BPD) in preterm infants. Macrolides have been used for the treatment of Ureaplasma spp. infection, with an intention to prevent BPD. The objective of this meta-analysis is to evaluate the use of macrolides in the prevention of BPD in preterm infants.. We searched MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials, abstracts of the major pediatric society meetings and bibliographies of retrieved articles. We included randomized controlled trials assessing the effects of macrolides therapy on BPD in preterm infants. A random/fixed-effect model was used to synthesize predefined outcomes.. Six studies involving 469 preterm infants were eligible for the analysis. Macrolides when used prophylactically (4 studies) did not show significant reduction in BPD (risk ratio, RR, 0.88, 95% confidence interval, CI, 0.75-1.03), death (RR 0.89, 95% CI 0.79-1.01) or in the composite outcome of BPD/death. Similarly, there was no significant reduction in BPD (RR 0.64, 95% CI 0.31-1.31) or the composite outcome of BPD/death (RR 0.41, 95% CI 0.05-3.13), when macrolides were used in Ureaplasma-positive infants. However, prophylactic azithromycin therapy (3 studies) was associated with significant reduction in BPD (RR 0.83, 95% CI 0.71-0.97; number needed to treat, NNT, 10) and composite outcome of BPD/death (RR 0.86, 95% CI 0.77-0.97; NNT 10).. This meta-analysis demonstrates prophylactic azithromycin therapy was associated with statistically significant reduction in BPD and the composite outcome of BPD/death in preterm infants. However, given the limited information on pharmacokinetics and potential harmful effects, further studies should be done before routine use of azithromycin in the neonatal population.

Topics: Anti-Bacterial Agents; Azithromycin; Bronchopulmonary Dysplasia; Chi-Square Distribution; Gestational Age; Humans; Infant; Infant Mortality; Infant, Newborn; Infant, Premature; Odds Ratio; Risk Factors; Treatment Outcome

Chronic lung disease of prematurity (CLD) remains a major cause of morbidity and mortality in preterm infants. Ureaplasma has received intermittent attention over the last two decades as a possible contributory factor. In addition, pulmonary inflammation is associated with the development of CLD. The macrolide azithromycin provides an attractive option to determine if it can decrease the development of CLD as it has both anti-inflammatory and anti-infective properties. In this article, the authors review the evidence for the role of Ureaplasma in the development of CLD and the obstacles faced in the development of a drug before it reaches clinical practice.

Topics: Anti-Bacterial Agents; Azithromycin; Bronchopulmonary Dysplasia; Drug Discovery; Humans; Infant, Newborn; Infant, Premature; Ureaplasma; Ureaplasma Infections

Preterm birth, especially at less than 30 weeks' gestation, is significantly associated with respiratory, neurodevelopmental and growth abnormalities. The AZTEC study has recruited 799 infants born at < 30 weeks' gestation to determine if a ten-day intravenous treatment with azithromycin improves survival without development of chronic lung disease of prematurity (CLD) at 36 weeks' post menstrual age (PMA) when compared to placebo. The follow-up studies will compare respiratory, neurodevelopmental and growth outcomes up to 2 years of corrected age between infants who received azithromycin and those who received placebo in the early neonatal period.. Survivors at 36 weeks' PMA from the main Azithromycin Therapy for Chronic Lung Disease of Prematurity (AZTEC) study with parental consent will continue to be followed up to discharge from the neonatal unit and to 2 years of corrected age. Length of stay, rates of home oxygen, length of supplemental oxygen requirement, hospital admissions, drug usage, respiratory illness, neurodevelopmental disability and death rates will be reported. Data is being collected via parentally completed respiratory and neurodevelopmental questionnaires at 1 and 2 years of corrected age respectively. Additional information is being obtained from various sources including hospital discharge and clinical letters from general practitioners and hospitals as well as from national databases including the National Neonatal Research Database and NHS Digital.. The AZTEC-FU study will assess mortality and important neonatal morbidities including respiratory, neurodevelopmental and growth outcomes. Important safety data will also be collected, including the incidence of potential consequences of early macrolide use, primarily pyloric stenosis. This study may have implications on future neonatal care.. The study was retrospectively registered on ISRCTN (ISRCTN47442783).

Topics: Azithromycin; Bronchopulmonary Dysplasia; Female; Follow-Up Studies; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Oxygen; Premature Birth; Randomized Controlled Trials as Topic

Macrolides have anti-inflammatory and immunomodulatory properties that give this class of antibiotics a role that differs from its classical use as an antibiotic, which opens new therapeutic possibilities.. The aim of this study was to evaluate the anti-inflammatory effect of azithromycin in preventing mechanical ventilation (MV)-induced lung injury in very-low-birth-weight preterm neonates.. This is a randomized, double-blind, placebo-controlled trial of preterm neonates who received invasive MV within 72 h of birth. Patients were randomized to receive intravenous azithromycin (at a dose of 10/mg/kg/day for 5 days) or placebo (0.9% saline) within 12 h of the start of MV. Two blood samples were collected (before and after intervention) for measurement of interleukins (ILs) and PCR for Ureaplasma. Patients were followed up throughout the hospital stay for the outcomes of death and broncho-pulmonary dysplasia defined as need for oxygen for a period of ≥28 days of life (registered at ClinicalTrials.gov, No. NCT03485703).. Forty patients were analyzed in the azithromycin group and 40 in the placebo group. Five days after the last dose, serum IL-2 and IL-8 levels dropped significantly in the azithromycin group. There was a significant reduction in the incidence of death and O2 dependency at 28 days/death in azithromycin-treated patients regardless of the detection of Ureaplasma in blood.. Azithromycin has anti-inflammatory effects, with a decrease in cytokines after 5 days of use and a reduction in death and O2 dependency at 28 days/death in mechanically ventilated preterm neonates.

Topics: Azithromycin; Bronchopulmonary Dysplasia; Humans; Infant, Newborn; Infant, Premature; Lung Injury; Respiration, Artificial

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.

Topics: Administration, Intravenous; Anti-Bacterial Agents; Azithromycin; Bronchopulmonary Dysplasia; Cytokines; Humans; Infant; Infant, Newborn; Infant, Premature; Inflammation; Microbial Sensitivity Tests; Nonlinear Dynamics; Respiratory Tract Infections; Treatment Outcome; Ureaplasma; Ureaplasma Infections

Ureaplasma respiratory tract colonization is associated with bronchopulmonary dysplasia (BPD) in preterm infants. Previously, we demonstrated that a single intravenous (i.v.) dose of azithromycin (10 mg/kg of body weight) is safe but inadequate to eradicate Ureaplasma spp. in preterm infants. We performed a nonrandomized, single-arm open-label study of the pharmacokinetics (PK) and safety of intravenous 20-mg/kg single-dose azithromycin in 13 mechanically ventilated neonates with a gestational age between 24 weeks 0 days and 28 weeks 6 days. Pharmacokinetic data from 25 neonates (12 dosed with 10 mg/kg i.v. and 13 dosed with 20 mg/kg i.v.) were analyzed using a population modeling approach. Using a two-compartment model with allometric scaling of parameters on body weight (WT), the population PK parameter estimates were as follows: clearance, 0.21 liter/h × WT(kg)(0.75) [WT(kg)(0.75) indicates that clearance was allometrically scaled on body weight (in kilograms) with a fixed exponent of 0.75]; intercompartmental clearance, 2.1 liters/h × WT(kg)(0.75); central volume of distribution (V), 1.97 liters × WT (kg); and peripheral V, 17.9 liters × WT (kg). There was no evidence of departure from dose proportionality in azithromycin exposure over the tested dose range. The calculated area under the concentration-time curve over 24 h in the steady state divided by the MIC90 (AUC24/MIC90) for the single dose of azithromycin (20 mg/kg) was 7.5 h. Simulations suggest that 20 mg/kg for 3 days will maintain azithromycin concentrations of >MIC50 of 1 μg/ml for this group of Ureaplasma isolates for ≥ 96 h after the first dose. Azithromycin was well tolerated with no drug-related adverse events. One of seven (14%) Ureaplasma-positive subjects and three of six (50%) Ureaplasma-negative subjects developed physiologic BPD. Ureaplasma was eradicated in all treated Ureaplasma-positive subjects. Simulations suggest that a multiple-dose regimen may be efficacious for microbial clearance, but the effect on BPD remains to be determined.

Topics: Anti-Bacterial Agents; Area Under Curve; Azithromycin; Body Weight; Bronchopulmonary Dysplasia; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Gestational Age; Humans; Infant, Newborn; Infant, Premature; Injections, Intravenous; Male; Microbial Sensitivity Tests; Models, Statistical; Respiratory System; Treatment Outcome; Ureaplasma

Since preventive therapies for bronchopulmonary dysplasia (BPD) are limited we treated preterm infants with azithromycin to decrease the incidence of BPD.. Infants less than 1,250 g birth weight were randomized to azithromycin or placebo within 12 hr of beginning mechanical ventilation and within 72 hr of birth. The treatment group received azithromycin 10 mg/kg/day for 7 days followed by 5 mg/kg/day for a maximum of 6 weeks. Aspirates were collected during the study to assay for Ureaplasma. The primary endpoints were incidence of BPD or mortality. (Clinical Trials Identifier: NCT00319956.). A total of 220 infants were enrolled (n=111 azithromycin, and 109 placebo). Mortality was 18% for the azithromycin group versus 22% for the placebo group (P = 0.45). Incidence of BPD was 76% for the azithromycin group versus 84% for the placebo group (P=0.2). The multiple logistic regression analysis demonstrated an odds ratio of 0.46 decrease in the chance of developing BPD or death for the azithromycin group, but was not statistically significant. The incidence of BPD in the Ureaplasma subgroup was 73% in the azithromycin group versus 94% in the placebo group (P=0.03). Analysis of patients in the Ureaplasma subgroup only, using the exact logistic model demonstrated a decrease in BPD or death in the azithromycin group with an estimated odds ratio of 0.026 (0.001-0.618, 95% confidence interval).. Routine use of azithromycin therapy for the prevention of BPD cannot be recommended. The early treatment of Ureaplasma colonized/infected patients might be beneficial, but a larger multi-centered trial is required to assess this more definitively.

Topics: Anti-Bacterial Agents; Azithromycin; Bronchopulmonary Dysplasia; Double-Blind Method; Female; Humans; Incidence; Infant, Newborn; Infant, Premature; Infant, Very Low Birth Weight; Male; Respiration, Artificial; Ureaplasma; Ureaplasma Infections

Azithromycin reduces the severity of illness in patients with inflammatory lung disease such as cystic fibrosis and diffuse panbronchiolitis. Bronchopulmonary dysplasia (BPD) is a pulmonary disorder which causes significant morbidity and mortality in premature infants. BPD is pathologically characterized by inflammation, fibrosis and impaired alveolar development. The purpose of this study was to obtain pilot data on the effectiveness and safety of prophylactic azithromycin in reducing the incidence and severity of BPD in an extremely low birth weight (< or = 1000 grams) population.. Infants < or = 1000 g birth weight admitted to the University of Kentucky Neonatal Intensive Care Unit (level III, regional referral center) from 9/1/02-6/30/03 were eligible for this pilot study. The pilot study was double-blinded, randomized, and placebo-controlled. Infants were randomized to treatment or placebo within 12 hours of beginning mechanical ventilation (IMV) and within 72 hours of birth. The treatment group received azithromycin 10 mg/kg/day for 7 days followed by 5 mg/kg/day for the duration of the study. Azithromycin or placebo was continued until the infant no longer required IMV or supplemental oxygen, to a maximum of 6 weeks. Primary endpoints were incidence of BPD as defined by oxygen requirement at 36 weeks gestation, post-natal steroid use, days of IMV, and mortality. Data was analyzed by intention to treat using Chi-square and ANOVA.. A total of 43 extremely premature infants were enrolled in this pilot study. Mean gestational age and birth weight were similar between groups. Mortality, incidence of BPD, days of IMV, and other morbidities were not significantly different between groups. Post-natal steroid use was significantly less in the treatment group [31% (6/19)] vs. placebo group [62% (10/16)] (p = 0.05). Duration of mechanical ventilation was significantly less in treatment survivors, with a median of 13 days (1-47 days) vs. 35 days (1-112 days)(p = 0.02).. Our study suggests that azithromycin prophylaxis in extremely low birth weight infants may effectively reduce post-natal steroid use for infants. Further studies are needed to assess the effects of azithromycin on the incidence of BPD and possible less common side effects, before any recommendations regarding routine clinical use can be made.

Topics: Anti-Bacterial Agents; Anti-Inflammatory Agents; Azithromycin; Bronchopulmonary Dysplasia; Double-Blind Method; Female; Humans; Infant, Extremely Low Birth Weight; Infant, Newborn; Male; Pilot Projects; Placebo Effect; Treatment Outcome

It is unclear whether Ureaplasma-associated pneumonia and azithromycin treatment affect the risk for bronchopulmonary dysplasia (BPD).. A retrospective cohort study was performed in very low birth weight (VLBW) infants who tested positive for Ureaplasma within 72 h after birth in a tertiary unit. Chest X-ray (CXR) and laboratory test were performed before and after azithromycin treatment. Multivariate logistic regression analysis was used to identify the independent association between BPD and Ureaplasma-associated pneumonia, as well as BPD and effective azithromycin treatment.. A total of 118 infants were included in the current study, of whom 36 developed BPD (defined as supplemental oxygen needed at postmenstrual age 36 weeks or discharge). The rate of BPD was significantly higher in infants with Ureaplasma-associated pneumonia (44.6%) compared to infants with Ureaplasma colonization (17.7%, P = 0.002). After adjusting for confounders, an effective azithromycin treatment was significantly associated with reduced risk of BPD [odd ratio (OR) 0.011; 95% confidence interval (CI): 0.000-0.250), whereas Ureaplasma-associated pneumonia was not significantly associated with BPD (OR 1.835; 95% CI: 0.548-6.147).. Effective Azithromycin treatment in Ureaplasma positive VLBW infants was associated with a reduced risk of BPD.

Topics: Azithromycin; Bronchopulmonary Dysplasia; Cohort Studies; Humans; Infant; Infant, Newborn; Infant, Premature; Retrospective Studies; Ureaplasma; Ureaplasma Infections

Topics: Anti-Bacterial Agents; Azithromycin; Bronchopulmonary Dysplasia; Humans; Infant; Infant, Newborn; Infant, Premature; Ureaplasma

Ureaplasma spp. in the maternal genitourinary tract has come to attention as a cause of preterm labor, spontaneous abortion, chorioamnionitis and adverse outcomes. A few controversies, however, still remain, namely, whether it should be treated aggressively or not. The aim of this study was to evaluate the effect of maternal azithromycin (AZ) treatment for Ureaplasma colonization on neonatal morbidities including bronchopulmonary dysplasia (BPD).. A retrospective case-control study of preterm babies delivered at ≤30 weeks of gestational age (GA) from 2012 to 2016 was conducted. Infants whose mothers had confirmed Ureaplasma colonization and treatment with AZ (m-AZ, cases) were matched by GA to control subjects whose mothers did not have Ureaplasma colonization. A subgroup analysis (nUU(+), infants with neonatal respiratory Ureaplasma colonization; nUU(-), infants without colonization) was also performed.. Fifty-five control subjects were matched to 110 m-AZ subjects. The incidence of preterm premature rupture of membranes (P = 0.003) and of moderate-severe BPD (P = 0.010) was significantly higher in the m-AZ group. On subgroup analysis with post-hoc analysis (m-AZ + nUU(+) [I, n = 55] vs m-AZ + nUU(-) [II, n = 55] vs controls [n = 55]), the incidence of moderate-severe BPD was significantly different: 26% (I) vs 22% (II) vs 7% (controls), P = 0.033.. Maternal Ureaplasma colonization was associated with moderate-severe BPD despite the use of AZ treatment. In addition, if the neonatal respiratory tract was colonized, then moderate-severe BPD developed even with maternal AZ treatment. Hence, selective antenatal and postnatal treatment of Ureaplasma colonization would be needed to control BPD development.

Topics: Anti-Bacterial Agents; Azithromycin; Bronchopulmonary Dysplasia; Case-Control Studies; Female; Female Urogenital Diseases; Fetal Membranes, Premature Rupture; Gestational Age; Humans; Incidence; Infant, Newborn; Infant, Premature; Pregnancy; Prenatal Exposure Delayed Effects; Respiratory Tract Infections; Retrospective Studies; Ureaplasma; Ureaplasma Infections

The optimal antibiotic regimen for preterm premature rupture of membrane (pPROM) is still unclear. This study aimed to determine the effects of ampicillin-sulbactam (SBT/ABPC) and azithromycin (AZM) on the incidence of bronchopulmonary dysplasia (BPD).. This retrospective study included women with singleton gestations and a diagnosis of pPROM between 22 and 27 weeks of gestation. In patients presenting with a high risk of intra-amniotic infection between January 2011 and May 2013, piperacillin or cefmetazole + clindamycin (regimen 1 group; n = 11) was administered, whereas SBT/ABPC and AZM (regimen 2 group; n = 11) were administered in patients presenting a similar risk between June 2013 and May 2016.. The incidence of moderate or severe infant BPD in the regimen 2 group was significantly lower than that in the regimen 1 group, even when adjusted for gestational age at the time of rupture of membrane, with an odds ratio (95% confidence interval) of 0.02 (1.8 × 10. In patients with pPROM between 22 and 27 weeks of gestation, the administration of SBT/ABPC and AZM may improve the perinatal outcomes.

Topics: Adult; Ampicillin; Anti-Bacterial Agents; Azithromycin; Bronchopulmonary Dysplasia; Cefmetazole; Clindamycin; Drug Therapy, Combination; Female; Fetal Membranes, Premature Rupture; Humans; Incidence; Outcome Assessment, Health Care; Piperacillin; Pregnancy; Retrospective Studies; Sulbactam

A survey was set up to gauge the opinions of neonatologists on the role of Ureaplasma in bronchopulmonary dysplasia (BPD) development, the use of azithromycin for BPD prevention, and the factors influencing azithromycin use in European neonatal intensive care units (NICUs). 167 NICUs participated in the survey, representing 28 European countries. For respondents, the two major perceived risk factors for BPD were prematurity of <28 weeks and high oxygen requirements. Only 38% of NICUs had a protocol for BPD prevention and 47% routinely tested for Ureaplasma. In cases of infection, macrolides were the first choice. Most (78%) NICUs were interested in participating in a trial evaluating azithromycin safety and efficacy in reducing BPD rates. Opinions and clinical practice varied between European neonatal units, and differences in Ureaplasma treatment and prevention of BPD highlight the need for further azithromycin evaluation and for improved therapeutic knowledge in preterms.

Topics: Anti-Bacterial Agents; Azithromycin; Bronchopulmonary Dysplasia; Data Collection; Europe; Humans; Infant, Newborn; Infant, Premature; Intensive Care Units, Neonatal; Risk Factors; Surveys and Questionnaires; Ureaplasma; Ureaplasma Infections

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.

Topics: Azithromycin; Bronchopulmonary Dysplasia; Female; Humans; Infant, Extremely Low Birth Weight; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Male; Respiration, Artificial; Ureaplasma; Ureaplasma Infections

Alveolar development comprises the transition of lung architecture from saccules to gas-exchange units during late gestation and early postnatal development. Exposure to hyperoxia disrupts developmental signaling pathways and causes alveolar hypoplasia as seen in bronchopulmonary dysplasia affecting preterm human newborns. Expanding literature suggests that epigenetic changes caused by environmental triggers during development may lead to heritable changes in gene expression. Given recent data on altered histone deacetylase (HDAC) activity in lungs of humans and animal models with airspace enlargement/emphysema, we hypothesized that alveolar hypoplasia from hyperoxia exposure in neonatal mice is a consequence of cell cycle arrest and reduced HDAC activity and up-regulation of the cyclin-dependent kinase inhibitor, p21. We exposed newborn mice to hyperoxia and compared lung morphologic and epigenetic changes to room air controls. Furthermore, we pretreated a subgroup of animals with the macrolide antibiotic azithromycin (AZM), known to possess antiinflammatory properties. Our results showed that hyperoxia exposure resulted in alveolar hypoplasia and was associated with decreased HDAC1 and HDAC2 and increased p53 and p21 expression. Furthermore, AZM did not confer protection against hyperoxia-induced alveolar changes. These findings suggest that alveolar hypoplasia caused by hyperoxia is mediated by epigenetic changes affecting cell cycle regulation/senescence during lung development.

Topics: Animals; Animals, Newborn; Anti-Inflammatory Agents; Azithromycin; Bronchopulmonary Dysplasia; Cell Proliferation; Cellular Senescence; Cyclin-Dependent Kinase Inhibitor p21; Disease Models, Animal; Down-Regulation; Epigenesis, Genetic; Histone Deacetylase 1; Histone Deacetylase 2; Humans; Hyperoxia; Infant, Newborn; Mice; Pulmonary Alveoli; Signal Transduction; Tumor Suppressor Protein p53; Up-Regulation

Nuclear factor-kappaB (NF-kappaB) plays a central role in regulating key proinflammatory mediators. The activation of NF-kappaB is increased in tracheal aspirate (TA) cells from premature infants developing bronchopulmonary dysplasia (BPD). We studied the effect of azithromycin (AZM) on the suppression of NF-kappaB activation and the synthesis of pro-inflammatory cytokines IL-6 and IL-8 by TA cells obtained from premature infants. Tracheal aspirate cells were stimulated with tumor necrosis factor-alpha (TNF-alpha) and incubated with AZM. The nuclear NF-kappaB-DNA binding activity, the levels of inhibitory kappaB-alpha (IkappaB-alpha) in the cytoplasmic fraction and IL-6 and IL-8 release in the cell culture media were measured. Stimulation of TA cells by TNF-alpha increased the activation of NF-kappaB, which was suppressed by the addition of AZM. Increased activation of NF-kappaB was also associated with increased levels of pro-inflammatory cytokines (IL-6 and IL-8). AZM significantly reduced the IL-6 and IL-8 production to the levels similar to control. TNF-alpha stimulation also increased the degradation of IkappaB-alpha, which was restored with the addition of AZM. Our data suggest that AZM therapy may be an effective alternative to steroids in reducing lung inflammation and prevention of BPD in ventilated premature infants.

Topics: Anti-Bacterial Agents; Azithromycin; Bronchopulmonary Dysplasia; Cell Count; Cells, Cultured; Dose-Response Relationship, Drug; Female; Gestational Age; Humans; I-kappa B Proteins; Infant, Newborn; Infant, Premature; Interleukin-6; Interleukin-8; Male; NF-kappa B; NF-KappaB Inhibitor alpha; Respiration, Artificial; Suction; Trachea; Tumor Necrosis Factor-alpha

Bronchopulmonary dysplasia (BPD) is a pulmonary disorder that causes significant morbidity and mortality in premature infants. BPD is pathologically characterized by inflammation, fibrosis, and mucosal necrosis, which leads to emphysematous coalescence of alveoli. We tested the hypothesis that azithromycin, a macrolide antibiotic, would decrease the severity of lung injury in an animal model of BPD. Sixty-three rat pups were randomly divided equally into control, hyperoxia, and hyperoxia plus azithromycin groups. The hyperoxia groups were exposed to > 95% oxygen from days of life 4 to 14. On day 14, the animals were processed for lung histology and tissue analysis. Lung morphology was assessed by mean linear intercept, a measure of alveolar size, with larger values corresponding to lungs that are more emphysematous. The degree of lung inflammation was assessed by quantifying interleukin-6 (IL-6) from lung homogenate. Fifty pups survived to day 14 (control = 21, hyperoxia = 11, hyperoxia + azithromycin = 18). Mortality was increased in the hyperoxia group versus the control group (p < .0001). Treatment with azithromycin improved survival in animals subjected to hyperoxia (p < .05). Azithromycin significantly decreased lung damage as determined by the mean linear intercept in the hyperoxia groups (p < .001). Finally, azithromycin-treated pups had lower levels of IL-6 in lung homogenate from the hyperoxia groups (p < .05). Azithromycin treatment resulted in improved survival, less emphysematous change, and decreased IL-6 levels in an animal model of BPD.

Topics: Animals; Animals, Newborn; Azithromycin; Bronchopulmonary Dysplasia; Disease Models, Animal; Humans; Hyperoxia; Infant, Newborn; Interleukin-6; Lung; Lung Injury; Rats; Rats, Sprague-Dawley