Adverse consequences of neonatal antibiotic exposure.

PURPOSE OF REVIEW: Antibiotics have not only saved lives and improved outcomes, but they also influence the evolving microbiome. This review summarizes reports on neonatal infections and variation in antibiotic utilization, discusses the emergence of resistant organisms, and presents data from human neonates and animal models demonstrating the impact of antibiotics on the microbiome, and how microbiome alterations impact health. The importance of antibiotic stewardship is also discussed. RECENT FINDINGS: Infections increase neonatal morbidity and mortality. Furthermore, the clinical presentation of infections can be subtle, prompting clinicians to empirically start antibiotics when infection is a possibility. Antibiotic-resistant infections are a growing problem. Cohort studies have identified extensive center variations in antibiotic usage and associations between antibiotic exposures and outcomes. Studies of antibiotic-induced microbiome alterations and downstream effects on the developing immune system have increased our understanding of the mechanisms underlying the associations between antibiotics and adverse outcomes. The emergence of resistant microorganisms and recent evidence linking antibiotic practice variations with health outcomes has led to the initiation of antibiotic stewardship programs. SUMMARY: The review encourages practitioners to assess local antibiotic use with regard to local microbiology, and to adopt steps to reduce infections and use antibiotics wisely.

Urine gastrin-releasing peptide in the first week correlates with bronchopulmonary dysplasia and post-prematurity respiratory disease.

RATIONALE: Bronchopulmonary dysplasia (BPD) is associated with post-prematurity respiratory disease (PRD) in survivors of extreme preterm birth. Identifying early biomarkers that correlate with later development of BPD and PRD may provide insights for intervention. In a preterm baboon model, elevated gastrin-releasing peptide (GRP) is associated with BPD, and GRP inhibition mitigates BPD occurrence. OBJECTIVE: We performed a prospective cohort study to investigate whether urine GRP levels obtained in the first postnatal week were associated with BPD, PRD, and other urinary biomarkers of oxidative stress. METHODS: Extremely low gestational age infants (23-28 completed weeks) were enrolled in a US multicenter observational study, The Prematurity and Respiratory Outcomes Program (http://clinicaltrials.gov/ct2/show/NCT01435187). We used multivariable logistic regression to examine the association between urine GRP in the first postnatal week and multiple respiratory outcomes: BPD, defined as supplemental oxygen use at 36 + 0 weeks postmenstrual age, and post-PRD, defined by positive quarterly surveys for increased medical utilization over the first year (PRD score). RESULTS: A total of 109 of 257 (42%) infants had BPD, and 120 of 217 (55%) had PRD. On adjusted analysis, GRP level more than 80 was associated with BPD (adjusted odds ratio [aOR], 1.83; 95% confidence interval [CI], 1.03-3.25) and positive PRD score (aOR, 2.46; 95% CI, 1.35-4.48). Urine GRP levels correlated with duration of NICU ventilatory and oxygen support and with biomarkers of oxidative stress: allantoin and 8-hydroxydeoxyguanosine. CONCLUSIONS: Urine GRP in the first postnatal week was associated with concurrent urine biomarkers of oxidative stress and with later diagnoses of BPD and PRD.

Postconception age and other risk factors associated with mortality following Gram-negative rod bacteremia.

BACKGROUND: Neonatal nosocomial Gram-negative rod bacteremia (GNR-b) is considered ominous. DESIGN: Multi-center cohort study of premature infants (N=6172) who had a blood culture after day of life 3 and whose birthweight was < or =1250 g. RESULTS: A total of 437 neonates developed GNR-b; most commonly with Klebsiella (122/437; 28%), Enterobacter (97/437; 22%), Escherichia coli (90/437; 21%), Pseudomonas (63/437; 14%), and Serratia (49/437; 11%). Neonates infected with Pseudomonas were more likely to die (21/63; 33%) than infants infected with other GNR (50/374; 13%). In multivariable logistic regression, infection with Pseudomonas, mechanical ventilation, and race were associated with subsequent mortality. Postconception age (PCA) was most strongly associated with mortality. Using neonates with >34 weeks PCA at the time of the first blood culture as the reference category, mortality was higher in neonates <26 weeks PCA (odds ratio (OR)=9.21; 95% confidence interval (CI)=2.79, 30.44), and in neonates 26 to 28 weeks PCA (OR=3.94; 95% CI=1.29, 12.03). CONCLUSIONS: Among premature infants, much of the mortality experienced in GNR-b is due to infection with Pseudomonas rather than enteric GNR. Race, the need for mechanical ventilation, and younger PCA when the blood culture was obtained were also strongly associated with mortality.

Mortality following blood culture in premature infants: increased with Gram-negative bacteremia and candidemia, but not Gram-positive bacteremia.

OBJECTIVE: To describe survival following nosocomial bloodstream infections and quantify excess mortality associated with positive blood culture. STUDY DESIGN: Multicenter cohort study of premature infants. RESULTS: First blood culture was negative for 4648/5497 (78%) of the neonates--390/4648 (8%) died prior to discharge. Mortality prior to discharge was 19% in the 161 infants with Gram-negative rod (GNR) bacteremia, 8% in the 854 neonates with coagulase negative staphylococcus (CONS), 6% in the 169 infants infected with other Gram-positive bacteria (GP-o), and 26% in the 115 neonates with candidemia. The excess 7-day mortality was 0% for Gram-positive organisms and 83% for GNR bacteremia and candidemia. Using negative blood culture as referent, GNR [hazard ratio (HR)=2.61] and candidemia (HR=2.27) were associated with increased mortality; CONS (HR=1.08) and GP-o (HR=0.97) were not. CONCLUSIONS: Nosocomial GNR bacteremia and candidemia were associated with increased mortality but Gram-positive bacteremia was not.

Use of medications for gastroesophageal reflux at discharge among extremely low birth weight infants.

OBJECTIVES: Our goals were (1) to determine the use of medications to treat gastroesophageal reflux in extremely low birth weight infants (birth weight of < 1000 g) at discharge; (2) to identify risk factors associated with the use of medications to treat gastroesophageal reflux at discharge; and (3) to assess the contribution of gastroesophageal reflux medication use at discharge to growth and development at corrected ages of 18 to 22 months. METHODS: This retrospective cohort analysis included extremely low birth weight infants enrolled at National Institute of Child Health and Human Development Neonatal Research Network Centers between 2002 and 2003 who survived to follow-up evaluations at corrected ages of 18 to 22 months. Analyses were used to identify factors associated with discharge with antireflux medications and poor growth or neurodevelopmental impairment after discharge. RESULTS: A total of 1598 infants were included in the analyses; 24.8% were discharged from the hospital with medications to treat gastroesophageal reflux. A total of 19.3% of the 1287 infants discharged at postmenstrual age of < or = 42 weeks were discharged with antireflux medications. For those infants, center, lower gestational age, and race had significant effects on the use of antireflux medications at discharge. A total of 47.6% of the 311 infants discharged at postmenstrual age of > 42 weeks were discharged with antireflux medications. For those infants, no tested variables were associated with treatment with antireflux medications at discharge. Use of antireflux medications at discharge was not associated with either poor growth or neurodevelopmental impairment at corrected ages of 18 to 22 months. CONCLUSIONS: Use of antireflux medications at the time of discharge seems to be common for extremely low birth weight infants, especially those discharged at postmenstrual age of > 42 weeks, but does not seem to have effects on growth or development at the time of follow-up evaluations.