Optimizing gentamicin conventional and extended interval dosing in neonates using Monte Carlo simulation - a retrospective study.

BACKGROUND: Although aminoglycosides are routinely used in neonates, controversy exists regarding empiric dosing regimens. The objectives were to determine gentamicin pharmacokinetics in neonates, and develop initial mg/kg dosing recommendations that optimized target peak and trough concentration attainment for conventional and extended-interval dosing (EID) regimens. METHODS: Patient demographics and steady-state gentamicin concentration data were retrospectively collected for 60 neonates with no renal impairment admitted to a level III neonatal intensive care unit. Mean pharmacokinetics were calculated and multiple linear regression was performed to determine significant covariates of clearance (L/h) and volume of distribution (L). Classification and regression tree (CART) analysis identified breakpoints for significant covariates. Monte Carlo Simulation (MCS) was used to determine optimal dosing recommendations for each CART-identified sub-group. RESULTS: Gentamicin clearance and volume of distribution were significantly associated with weight at gentamicin initiation. CART-identified breakpoints for weight at gentamicin initiation were: ≤ 850 g, 851-1200 g, and > 1200 g. MCS identified that a conventional dose of gentamicin 3.5 mg/kg given every 48 h or an EID of 8-9 mg/kg administered every 72 h in neonates weighing ≤ 850 g, and every 24 and 48 h, respectively, in neonates weighing 851-1200 g, provided the best probability of attaining conventional (peak: 5-10 mg/L and trough: ≤ 2 mg/L) and EID targets (peak:12-20 mg/L, trough:≤ 0.5 mg/L). Insufficient sample size in the > 1200 g neonatal group precluded further investigation of this weight category. CONCLUSIONS: This study provides initial gentamicin dosing recommendations that optimize target attainment for conventional and EID regimens in neonates weighing ≤ 1200 g. Prospective validation and empiric dose optimization for neonates > 1200 g is needed.

Development, evaluation and validation of a screening tool for late onset bacteremia in neonates - a pilot study.

BACKGROUND: Clinical and laboratory parameters can aid in the early identification of neonates at risk for bacteremia before clinical deterioration occurs. However, current prediction models have poor diagnostic capabilities. The objective of this study was to develop, evaluate and validate a screening tool for late onset (> 72 h post admission) neonatal bacteremia using common laboratory and clinical parameters; and determine its predictive value in the identification of bacteremia. METHODS: A retrospective chart review of neonates admitted to a neonatal intensive care unit (NICU) between March 1, 2012 and January 14, 2015 and a prospective evaluation of all neonates admitted between January 15, 2015 and March 30, 2015 were completed. Neonates with late-onset bacteremia (> 72 h after NICU admission) were eligible for inclusion in the bacteremic cohort. Bacteremic patients were matched to non-infected controls on several demographic parameters. A Pearson's Correlation matrix was completed to identify independent variables significantly associated with infection (p < 0.05, univariate analysis). Significant parameters were analyzed using iterative binary logistic regression to identify the simplest significant model (p < 0.05). The predictive value of the model was assessed and the optimal probability cut-off for bacteremia was determined using a Receiver Operating Characteristic curve. RESULTS: Maximum blood glucose, heart rate, neutrophils and bands were identified as the best predictors of bacteremia in a significant binary logistic regression model. The model's sensitivity, specificity and accuracy were 90, 80 and 85%, respectively, with a false positive rate of 20% and a false negative rate of 9.7%. At the study bacteremia prevalence rate of 51%, the positive predictive value, negative predictive value and negative post-test probability were 82, 89 and 11%, respectively. CONCLUSION: The model developed in the current study is superior to currently published neonatal bacteremia screening tools. Validation of the tool in a historic data set of neonates from our institution will be completed.

Determination of vancomycin pharmacokinetics in neonates to develop practical initial dosing recommendations.

Variability in neonatal vancomycin pharmacokinetics and the lack of consensus for optimal trough concentrations in neonatal intensive care units pose challenges to dosing vancomycin in neonates. Our objective was to determine vancomycin pharmacokinetics in neonates and evaluate dosing regimens to identify whether practical initial recommendations that targeted trough concentrations most commonly used in neonatal intensive care units could be determined. Fifty neonates who received vancomycin with at least one set of steady-state levels were evaluated retrospectively. Mean pharmacokinetic values were determined using first-order pharmacokinetic equations, and Monte Carlo simulation was used to evaluate initial dosing recommendations for target trough concentrations of 15 to 20 mg/liter, 5 to 20 mg/liter, and ≤20 mg/liter. Monte Carlo simulation revealed that dosing by mg/kg of body weight was optimal where intermittent dosing of 9 to 12 mg/kg intravenously (i.v.) every 8 h (q8h) had the highest probability of attaining a target trough concentration of 15 to 20 mg/liter. However, continuous infusion with a loading dose of 10 mg/kg followed by 25 to 30 mg/kg per day infused over 24 h had the best overall probability of target attainment. Initial intermittent dosing of 9 to 15 mg/kg i.v. q12h was optimal for target trough concentrations of 5 to 20 mg/liter and ≤20 mg/liter. In conclusion, we determined that the practical initial vancomycin dose of 10 mg/kg vancomycin i.v. q12h was optimal for vancomycin trough concentrations of either 5 to 20 mg/liter or ≤20 mg/liter and that the same initial dose q8h was optimal for target trough concentrations of 15 to 20 mg/liter. However, due to large interpatient vancomycin pharmacokinetic variability in neonates, monitoring of serum concentrations is recommended when trough concentrations between 15 and 20 mg/liter or 5 and 20 mg/liter are desired.

Effect of clinical and histological chorioamnionitis on the outcome of preterm infants.

Chorioamnionitis contributes to neonatal and maternal morbidity and mortality. We aimed to evaluate of the impact of clinical and histological chorioamnionitis on mortality and morbidity of preterm infants. Maternal and neonatal data were collected in a retrospective cohort of preterm infants less than 30 weeks' gestation. Infants were divided into three groups: those born to mothers with clinical chorioamnionitis, histological chorioamnionitis, or no chorioamnionitis. Of 274 identified preterm infants, 33 infants were born to mothers with clinical chorioamnionitis, 95 to mothers with histological chorioamnionitis, and 146 to mothers with no chorioamnionitis. Data were available for 180 (78%) of the 230 survivors at 18 months corrected age. Infants in the study groups were similar in gestational age, birth weight, and sex distribution. Clinical and histological chorioamnionitis were not predictive of infant mortality, cerebral palsy, bronchopulmonary dysplasia, periventricular leukomalacia, or retinopathy of prematurity. Infants in the clinical chorioamnionitis group had significantly lower cognitive (88 ± 10), language (82 ± 12), and motor (89 ± 11) scores compared with infants in the histological chorioamnionitis group (101 ± 13, p < 0.01; 91 ± 13, p < 0.05; and 99 ± 13, p < 0.05, respectively) and to infants in the no chorioamnionitis group (99 ± 13, p < 0.01; 92 ± 15, p < 0.05; and 97 ± 13, p < 0.05, respectively). Clinical chorioamnionitis is associated with developmental delay in preterm infants despite adequate treatment.

Role of ascorbate in lung cellular toxicity mediated by light-exposed parenteral nutrition solution.

Neonatal lung injury has been induced experimentally by infusion of multivitamin-containing light-exposed parenteral nutrition (PN) solutions. The objective was to explore the role of ascorbate in toxic effects of light-exposed PN on primary cultured foetal rat lung epithelial cells. Hydroperoxides were measured in 3% amino acid solutions at baseline, immediately after addition of either multivitamins or ascorbate alone (400 µg/mL) and again after a 24-h period of exposure to (or protection from) ambient light. Cellular toxicity was assessed by [C(14)]adenine release. Multivitamins or ascorbate alone increased hydroperoxides in PN, which was attenuated by light protection. Light-exposed PN containing multivitamins was more toxic to cells than baseline or light-protected PN. Exposure to ascorbate at concentrations both lower (< 5 µg/mL) and higher (> 1000 µg/mL) than normally contained in PN-induced oxidant-mediated cell death, as indicated by protective effects of hydroperoxide and hydroxyl radical scavengers. This study concludes that ascorbate generates toxic amounts of peroxide in PN solutions. The types and physiological importance of hydroperoxides induced by pro-oxidant effects of ascorbate require further evaluation in vivo.