Robert M. Ward

Neonatal complications following preterm birth

Improvements in neonatal intensive care during the last 20 years have increased the survival of the most immature newborns at 23 weeks from 0% to 65% at some centres, although rates vary widely among neonatal care centres. University of Utah, USA data show that each week in utero after week 23 raises survival by 6–9%, to 90% by 27–28 weeks and 95% by 33 weeks. Provision of care in specialised centres to provide high‐risk obstetric and neonatal intensive care, prenatal treatment with corticosteroids, postnatal treatment with surfactant and nitric oxide, and improvements in respirators and equipment to care for extremely immature infants all contribute to these changes. The increased rate of survival for extremely premature newborns has not been accompanied by an increased rate of severe intraventricular haemorrhage or neurological impairment, such as cerebral palsy. Regardless, intraventricular haemorrhage remains a significant problem, especially if associated with post‐haemorrhagic hydrocephalus, leading to long‐term neurological impairment and decreased survival. Necrotising enterocolitis (NEC) is more common in premature than in term newborns and is the most frequent cause of short bowel syndrome in infancy. Survival after surgery for NEC has improved during the last two decades, but complications of nutritional support produce many long‐term problems. Retinopathy of prematurity (ROP) remains a frequent cause of neurosensory impairment for extremely premature newborns. Laser photocoagulation for advanced ROP is more effective than cryotherapy for preventing retinal detachment and improving visual outcomes. Despite prenatal corticosteroid treatment and postnatal surfactant administration, many extremely premature newborns still develop bronchopulmonary dysplasia. Abnormal pulmonary function may persist into adulthood, but newer ventilators and management schemes appear to be reducing this long‐term morbidity. Many changes in neonatal care occur each year, but carefully controlled outcome studies are needed to evaluate the effectiveness of these newer styles of neonatal intensive care.

Population Pharmacokinetics of Fluconazole in Young Infants

ABSTRACT Fluconazole is being increasingly used to prevent and treat invasive candidiasis in neonates, yet dosing is largely empirical due to the lack of adequate pharmacokinetic (PK) data. We performed a multicenter population PK study of fluconazole in 23- to 40-week-gestation infants less than 120 days of age. We developed a population PK model using nonlinear mixed effect modeling (NONMEM) with the NONMEM algorithm. Covariate effects were predefined and evaluated based on estimation precision and clinical significance. We studied fluconazole PK in 55 infants who at enrollment had a median (range) weight of 1.02 (0.440 to 7.125) kg, a gestational age at birth (BGA) of 26 (23 to 40) weeks, and a postnatal age (PNA) of 2.3 (0.14 to 12.6) weeks. The final data set contained 357 samples; 217/357 (61%) were collected prospectively at prespecified time intervals, and 140/357 (39%) were scavenged from discarded clinical specimens. Fluconazole population PK was best described by a one-compartment model with covariates normalized to median values. The population mean clearance (CL) can be derived for this population by the equation CL (liter/h) equals 0.015 · (weight/1)0.75 · (BGA/26)1.739 · (PNA/2)0.237 · serum creatinine (SCRT)−4.896 (when SCRT is >1.0 mg/dl), and using a volume of distribution (V) (liter) of 1.024 · (weight/1). The relative standard error around the fixed effects point estimates ranged from 3 to 24%. CL doubles between birth and 28 days of age from 0.008 to 0.016 and from 0.010 to 0.022 liter/kg/h for typical 24- and 32-week-gestation infants, respectively. This population PK model of fluconazole discriminated the impact of BGA, PNA, and creatinine on drug CL. Our data suggest that dosing in young infants will require adjustment for BGA and PNA to achieve targeted systemic drug exposures.

Fluconazole dosing for the prevention or treatment of invasive candidiasis in young infants.

Background: Young infants are susceptible to developmental factors influencing the pharmacokinetics of drugs. Fluconazole is increasingly used to prevent and treat invasive candidiasis in infants. Dosing guidance remains empiric and variable because limited pharmacokinetic data exist. Methods: Our population pharmacokinetic model derived from 357 fluconazole plasma concentrations from 55 infants (23–40 week gestation) illustrates expected changes in fluconazole clearance based upon gestational age, postnatal age, weight, and creatinine. We used a Monte Carlo simulation approach based on parametric description of a patient populations pharmacokinetic response to fluconazole to predict fluconazole exposure (median: 10th and 90th percentile population variability range) after 3, 6, and 12 mg/kg dosing. Results: For the treatment of invasive candidiasis, a dose of at least 12 mg/kg/d in the first 90 days after birth is needed to achieve an area under the concentration curve (AUC) of >400 mg*h/L and an AUC/minimum inhibitory concentration (MIC) >50 for Candida species with MIC <8 &mgr;g/mL in ≥90% of <30 week gestation infants and 80% of 30 to 40 week gestation infants. The more preterm infants achieve a higher median AUC (682 mg*hr/L) compared with more mature infants (520 mg*hr/L). For early prevention of candidiasis in 23 to 29 week infants, a dose of 3 or 6 mg/kg twice weekly during the first 42 days of life is equivalent to an AUC of 50 and 100 mg*hr/L, respectively, and maintains fluconazole concentrations ≥2 or 4 &mgr;g/mL, respectively, for half of the dosing interval. For late prevention, the 6 mg/kg dose every 72 hours provides similar exposure to 3 mg/kg daily dose. Infants with serum creatinine ≥1.3 mg/dL have delayed drug clearance and dose adjustment is indicated if creatinine does not improve within 96 hours. Conclusions: A therapeutic concentration of fluconazole in premature infants with invasive candidiasis requires dosing substantially greater than commonly recommended in most reference texts. To prevent invasive candidiasis, twice weekly prophylaxis regimens can provide adequate exposure when unit specific MICs are taken into account.

A randomized, double-blind, placebo- controlled trial on intravenous ibuprofen L-lysine for the early closure of nonsymptomatic patent ductus arteriosus within 72 hours of birth in extremely low-birth-weight infants

A multicenter, double-blind, randomized, placebo-controlled trial was conducted to evaluate the efficacy and safety of intravenous (IV) ibuprofen (L-lysine) for the early closure of nonsymptomatic patent ductus arteriosus (PDA) within 72 hours of birth in extremely low-birth-weight (ELBW) infants with evidence of ductal shunting by echocardiogram. Eleven sites enrolled 136 infants with nonsymptomatic early PDA (gestational age < 30 weeks; body weight 500 to 1000 g) to receive a 3-day course (10 mg/kg, 5 mg/kg, and 5 mg/kg) of IV ibuprofen ( N = 68) or placebo ( N = 68). Cardiac echocardiogram was performed on study days 1 and 14, and with rescue. Infants were followed to 36 weeks postconceptional age. Patient demographics, mean (standard deviation), were similar between ibuprofen and placebo: birth weight: 798.5 g (128.7) versus 797.3 g (132.8); gestational age: 26.1 weeks (1.3) versus 26.2 weeks (1.4); and age at first dose: 1.5 days (0.7). The intent-to-treat analysis of the primary endpoint, subjects rescued, died, or dropped through study day 14, was 21/68 (30.9%) with ibuprofen and 36/68 (52.9%) for placebo ( P = 0.005). Death, intraventricular hemorrhage, necrotizing enterocolitis, daily fluid intake/output, liver function, bronchopulmonary dysplasia, and retinopathy of prematurity did not differ. A trend toward decreased periventricular leukomalacia by ibuprofen was noted. IV ibuprofen was effective and safe in the early closure of PDA in preterm neonates.

Cisapride disposition in neonates and infants: in vivo reflection of cytochrome P450 3A4 ontogeny

Cisapride, a prokinetic agent and substrate for cytochrome P450 (CYP) 3A4, has been used to treat neonates and infants with feeding intolerance and apnea or bradycardia associated with gastroesophageal reflux. At age 1 month, CYP3A4 activity has been reported to be only 30% to 40% of adult activity. This known developmental delay in the expression of CYP3A4 prompted us to conduct a classical open‐label pharmacokinetic study of cisapride in neonates and young infants.

Population pharmacokinetics of meropenem in plasma and cerebrospinal fluid of infants with suspected or complicated intra-abdominal infections

Background: Suspected or complicated intra-abdominal infections are common in young infants and lead to significant morbidity and mortality. Meropenem is a broad-spectrum antimicrobial agent with excellent activity against pathogens associated with intra-abdominal infections in this population. The purpose of this study was to determine the pharmacokinetics (PK) of meropenem in young infants as a basis for optimizing dosing and minimizing adverse events. Methods: Premature and term infants <91 days old hospitalized in 24 neonatal intensive care units were studied. Limited PK sampling was performed following single and multiple doses of meropenem 20 to 30 mg/kg of body weight every 8 to 12 hours based on postnatal and gestational age at birth. Population and individual patient (Bayesian) PK parameters were estimated using NONMEM. Results: In this study, 200 infants were enrolled and received the study drug. Of them, 188 infants with 780 plasma meropenem concentrations were analyzed. Their median (range) gestational age at birth and postnatal age at PK evaluation were 28 (23–40) weeks and 21 (1–92) days, respectively. In the final PK model, meropenem clearance was strongly associated with serum creatinine and postmenstrual age (clearance [L/h/kg] = 0.12*[(0.5/serum creatinine)**0.27]*[(postmenstrual age/32.7)**1.46]). Meropenem concentrations remained >4 &mgr;g/mL for 50% of the dose interval and >2 &mgr;g/mL for 75% of the dose interval in 96% and 92% of patients, respectively. The estimated penetration of meropenem into the cerebrospinal fluid was 70% (5–148). Conclusions: Meropenem dosing strategies based on postnatal and gestational age achieved therapeutic drug exposure in almost all infants.

UGT1A9, UGT2B7, and MRP2 genotypes can predict mycophenolic acid pharmacokinetic variability in pediatric kidney transplant recipients.

Background: Mycophenolic acid (MPA) exposure in pediatric patients with kidney transplant receiving body surface area (BSA)–based dosing exhibits large variability. Several genetic variants in glucuronosyltransferases (UGTs) and of multidrug resistance–associated protein 2 (MRP2) have independently been suggested to predict MPA exposure in adult patients with varying results. Here, the combined contribution of these genetic variants to MPA pharmacokinetic variability was investigated in pediatric renal transplant recipients who were on mycophenolic mofetil maintenance therapy. Methods: MPA and MPA-glucuronide concentrations from 32 patients were quantified by high-performance liquid chromatography. MPA exposure (AUC) was estimated using a 4-point abbreviated sampling strategy (predose/trough and 20 minutes, 1 hour, and 3 hours after dose) using a validated pediatric Bayesian estimator. Genotyping was performed for all of the following single nucleotide polymorphisms (SNPs): UGT1A8 830G>A(*3), UGT1A9 98T>C(*3), UGT1A9-440C>T, UGT1A9-2152C>T, UGT1A9-275T>A, UGT2B7-900A>G, and MRP2-24T>C. Results: Recipients heterozygous for MRP2-24T>C who also had UGT1A9-440C>T or UGT2B7-900A>G (n = 4), and MRP2-24T>C-negative recipients having both UGT1A9-440C>T and UGT2B7-900A>G (n = 5) showed a 2.2 and 1.7 times higher dose-dependent and BSA-normalized MPA-AUC compared with carriers of no or only 1 UGT-SNP (P < 0.001 and P = 0.01, respectively) (n = 7). Dose-dependent and BSA-normalized predose MPA concentrations were 3.0 and 2.4 times higher, respectively (P < 0.001). Interindividual variability in peak concentrations could be explained by the presence of the UGT1A9-440C>T genotype (P < 0.05). Conclusion: Our preliminary study demonstrates that combined UGT1A9-440C>T, UGT2B7-900A>G, and MRP2-24T>C polymorphisms can be important predictors of interindividual variability in MPA exposure in the pediatric population.

Fluticasone propionate pharmacogenetics: CYP3A4*22 polymorphism and pediatric asthma control

OBJECTIVE To determine the relationship between allelic variations in genes involved in fluticasone propionate (FP) metabolism and asthma control among children with asthma managed with inhaled FP. STUDY DESIGN The relationship between variability in asthma control scores and genetic variation in drug metabolism was assessed by genotyping 9 single nucleotide polymorphisms in the CYP3A4, CYP3A5, and CYP3A7 genes. Genotype information was compared with asthma control scores (0=well controlled to 15=poorly controlled), determined using a questionnaire modified from the National Heart Lung and Blood Institutes Expert Panel 3 guidelines. RESULTS Our study cohort comprised 734 children with asthma (mean age, 8.8±4.3 years) and was predominantly male (61%) and non-Hispanic white (53%). More than one-half of the children (56%; n=413) were receiving an inhaled glucocorticoid daily, with FP the most frequently prescribed agent (65%). Among the children receiving daily FP, single nucleotide polymorphisms in CYP3A5 and CYP3A7 were not associated with asthma control scores. In contrast, asthma control scores were significantly improved in the 20 children (7%) with the CYP3A4*22 allele (median, 3; range, 0-6) compared with the 201 children without the CYP3A4*22 allele (median, 4; range, 0-15; P=.02). The presence of CYP3A4*22 was associated with improved asthma control scores by 2.1 points (95% CI, 0.5-3.8). CONCLUSION The presence of CYP3A4*22, which is associated with decreased hepatic CYP3A4 expression and activity, was accompanied by improved asthma control in the FP-treated children. Decreased CYP3A4 activity may improve asthma control with inhaled FP.

Familial congenital non-immune hydrops, chylothorax, and pulmonary lymphangiectasia

Pulmonary lymphangiectasia is an uncommon congenital anomaly, and familial occurrence has rarely been reported. We report on two sibs with bilateral pleural effusion/chylothorax and hydrops who died neonatally. One sib required prenatal intrauterine hemithoracic drainage. Autopsy confirmed congenital pulmonary lymphangiectasia (CPL) histologically in the first case. Hydrops, characterized as subcutaneous edema and effusions in two or more body cavities, may be due to a variety of factors, but the co‐occurrence of CPL in one of these sibs, although rare, supports the notion that chylothorax and hydrops may be caused by structural lesions of lymph channels. Although most cases of CPL are sporadic, the reported sibs support autosomal recessive inheritance, with intrafamilial variability of a lymphatic disorder on a genetic basis. Mutations in vascular endothelial growth factor receptor‐3 (VEGFR3) in families with Milroy disease, mutations of FOXC2 in the lymphedema‐distichiasis syndrome, and fatal chylothorax in α9‐deficient mice are potential candidate genes.

Safety and effectiveness of meropenem in infants with suspected or complicated intra-abdominal infections.

BACKGROUND Intra-abdominal infections are common in young infants and lead to significant morbidity and mortality. Meropenem is a broad-spectrum antimicrobial with excellent activity against pathogens associated with intra-abdominal infections. The purpose of this study was to determine the safety and effectiveness of meropenem in young infants with suspected or complicated intra-abdominal infections. METHODS Preterm and term infants <91 days of age with suspected or confirmed intra-abdominal infections hospitalized in 24 neonatal intensive care units were studied in an open-label, multiple-dose study. Adverse events and serious adverse events were collected through 3 and 30 days following the last meropenem dose, respectively. Effectiveness was assessed by 3 criteria: death, bacterial cultures, and presumptive clinical cure score. RESULTS Of 200 subjects enrolled in the study, 99 (50%) experienced an adverse event, and 34 (17%) had serious adverse events; no adverse events were probably or definitely related to meropenem. The most commonly reported adverse events were sepsis (6%), seizures (5%), elevated conjugated bilirubin (5%), and hypokalemia (5%). Only 2 of the serious adverse events were determined to be possibly related to meropenem (isolated ileal perforation and an episode of fungal sepsis). Effectiveness was evaluable in 192 (96%) subjects, and overall treatment success was 84%. CONCLUSIONS Meropenem was well tolerated in this cohort of critically ill infants, and the majority of infants treated with meropenem met the definition of therapeutic success. CLINICAL TRIALS REGISTRATION NCT00621192.