Search tips
Search criteria

Results 1-9 (9)

Clipboard (0)

Select a Filter Below

Year of Publication
Document Types
1.  Effect of fluconazole prophylaxis on candidiasis and mortality in premature infants: A randomized clinical trial 
Invasive candidiasis in premature infants causes mortality and neurodevelopmental impairment. Fluconazole prophylaxis reduces candidiasis, but its effect on mortality and the safety of fluconazole is unknown.
To evaluate the efficacy and safety of fluconazole in preventing death or invasive candidiasis in extremely low-birth-weight infants.
This study was a randomized, blinded, placebo-controlled trial of fluconazole in premature infants. Infants weighing less than 750 g at birth (N = 361) from 32 neonatal intensive care units (NICUs) in the United States were randomly assigned to receive either fluconazole or placebo twice weekly for 42 days. Surviving infants were evaluated at 18 to 22 months corrected age for neurodevelopmental outcomes. The study was conducted between November 2008 and February 2013.
Fluconazole (6 mg/kg of body weight) or placebo.
The primary end point was a composite of death or definite or probable invasive candidiasis prior to study day 49 (1 week after completion of study drug). Secondary and safety outcomes included invasive candidiasis, liver function, bacterial infection, length of stay, intracranial hemorrhage, periventricular leukomalacia, chronic lung disease, patent ductus arteriosus requiring surgery, retinopathy of prematurity requiring surgery, necrotizing enterocolitis, spontaneous intestinal perforation, and neurodevelopmental outcomes—defined as a Bayley-III cognition composite score of less than 70, blindness, deafness, or cerebral palsy at 18–22-months corrected age.
Among infants receiving fluconazole, the composite primary end point of death or invasive candidiasis was 16% (95% CI, 11%–22%) vs 21% in the placebo group (95% CI, 15%–28%; odds ratio 0.73 [95% CI 0.43–1.23]; P=.24; treatment difference −5% [95% CI, −13%–3%]). Invasive candidiasis occurred less frequently in the fluconazole group (3% [95% CI, 1%–6%] vs the placebo group (9% [95% CI, 5%–14%]; P=.02; treatment difference −6% [95% CI, −11%–−1%]). The cumulative incidences of other secondary outcomes were not statistically different between groups. Neurodevelopmental impairment did not differ between the groups (fluconazole 31% [95% CI, 21–41%] vs placebo, 27% [95% CI, 18–37%]; P=.60; treatment difference 4% [95% CI, −10–17%]).
Among infants with a birth weight of less 750 g, 42 days of fluconazole prophylaxis compared with placebo did not result in a lower incidence of the composite of death or invasive candidiasis. These findings do not support the universal use of prophylactic fluconazole in extremely-low-birth-weight infants.
PMCID: PMC4110724  PMID: 24794367
2.  Predictors for the Development of Referral-Warranted Retinopathy of Prematurity in the Telemedicine Approaches to Evaluating Acute-Phase Retinopathy of Prematurity (e-ROP) Study 
JAMA ophthalmology  2015;133(3):304-311.
Detection of treatment-requiring retinopathy of prematurity (ROP) involves serial eye examinations. An ROP prediction model using predictive factors could identify high-risk infants and reduce required eye examinations.
To determine predictive factors for the development of referral-warranted (RW) ROP.
Design, Setting, and Participants
This multicenter observational cohort study included secondary analysis of data from the Telemedicine Approaches to Evaluating Acute-Phase Retinopathy of Prematurity Study. Infants included in the study had a birth weight (BW) of less than 1251 g.
Serial ROP examinations of premature infants who had 2 or more ROP examinations.
Main Outcomes and Measures
Incidence of RW-ROP (defined as the presence of plus disease, zone I ROP, or ROP stage 3 or greater in either eye) and associations with predictive factors.
Among 979 infants without RW-ROP at first study-related eye examination (median postmenstrual age, 33 weeks; range, 29-40 weeks) who underwent at least 2 eye examinations, 149 (15.2%) developed RW-ROP. In a multivariate model, significant predictors for RW-ROP were male sex (odds ratio [OR], 1.80; 95% CI, 1.13-2.86 vs female), nonblack race (OR, 2.76; 95% CI, 1.50-5.08 for white vs black race and OR, 4.81; 95% CI, 2.19-10.6 for other vs black race), low BW (OR, 5.16; 95% CI, 1.12-7.20 for ≤500 g vs >1100 g), younger gestational age (OR, 9.79; 95% CI, 3.49-27.5 for ≤24 weeks vs ≥28 weeks), number of quadrants with preplus disease (OR, 7.12; 95% CI, 2.53-20.1 for 1-2 quadrants and OR, 18.4; 95% CI, 4.28-79.4 for 3-4 quadrants vs no preplus disease), stage 2 ROP (OR, 4.13; 95% CI, 2.13-8.00 vs no ROP), the presence of retinal hemorrhage (OR, 4.36; 95% CI, 1.57-12.1 vs absence), the need for respiratory support (OR, 4.99; 95% CI, 1.89-13.2 for the need for controlled mechanical ventilator; OR, 11.0; 95% CI, 2.26-53.8 for the need for high-frequency oscillatory ventilation vs no respiratory support), and slow weight gain (OR, 2.44; 95% CI, 1.22-4.89 for weight gain ≤12 g/d vs >18 g/d). These characteristics predicted the development of RW-ROP significantly better than BW and gestational age (area under receiver operating characteristic curve, 0.88 vs 0.78; P < .001).
Conclusions and Relevance
When controlling for very low BW and prematurity, the presence of preplus disease, stage 2 ROP, retinal hemorrhage, and the need for ventilation at time of first study-related eye examination were strong independent predictors for RW-ROP. These predictors may help identify infants in need of timely eye examinations.
PMCID: PMC4416963  PMID: 25521746
3.  Pharmacokinetics and Safety of Fluconazole in Young Infants Supported with Extracorporeal Membrane Oxygenation 
Candida infections are a leading cause of infectious disease-related death in infants supported with extracorporeal membrane oxygenation (ECMO). The ECMO circuit can alter drug pharmacokinetics (PK), thus standard fluconazole dosing in children on ECMO may result in suboptimal drug exposure. This study determined the PK of fluconazole in infants on ECMO.
Infants <120 days old received either intravenous fluconazole prophylaxis (25 mg/kg once a week) or treatment (12 mg/kg daily) while on ECMO. Paired plasma samples were collected pre- and post-oxygenator around doses 1 and 2 to calculate PK indices and describe oxygenator extraction. A 1-compartment model was fit to the data using non-linear regression. Surrogate pharmacodynamic targets for efficacy were evaluated.
Ten infants were enrolled. After dose 1 (n=9), the median clearance was 17 mL/kg/h, the median volume of distribution was 1.5 L/kg, and the median exposure in the first 24 hours (AUC0–24) was 322 h*mg/L. After multiple doses (n=7), the median clearance was 22 mL/kg/h, the median volume of distribution was 1.9 L/kg, and the AUC0–24 was 352 h*mg/L. After dose 1, 78% of infants achieved the prophylaxis target, while only 11% achieved the therapeutic target. Oxygenator extraction of fluconazole was minimal (−2.0%, standard deviation 15.0), and extraction was not correlated with age of the ECMO circuit (rho= − 0.05). There were no adverse events related to fluconazole.
Infants on ECMO had higher volume of distribution but similar clearance when compared with historical controls not on ECMO. In infants on ECMO, a fluconazole dose of 25 mg/kg weekly provides adequate exposure for prophylaxis against Candida infections. However, higher doses may be needed for treatment.
PMCID: PMC3444624  PMID: 22627870
fluconazole; Candida; extracorporeal membrane oxygenation; pharmacokinetics; infants
4.  Safety of Oseltamivir Compared With the Adamantanes in Children Less Than 12 Months of Age 
When oseltamivir is administered in extremely high doses (500–1000 mg/kg) to young juvenile rats, central nervous system toxicity and death occurred in some animals. Mortality was not observed in older juvenile rats, suggesting a possible relationship between neurotoxicity and an immature blood-brain barrier. To assess potential neurologic adverse effects of oseltamivir use in infants, a retrospective chart review was performed in infants less than 12 months of age who received oseltamivir, amantadine, or rimantadine.
The primary objective was to describe the frequency of neurologic adverse events among children less than 12 months of age who received oseltamivir compared with those receiving adamantanes. Medical record databases, emergency department databases, and/or pharmacy records at 15 medical centers were searched to identify patients.
Of the 180 infants identified as having received antiviral therapy, 115 (64%) received oseltamivir, 37 (20%) received amantadine, and 28 (16%) received rimantadine. The median dose of oseltamivir was 2.0 mg/kg/dose in 3- to 5-month-old and 2.2 mg/kg/dose in 9- to 12-month-old infants. The maximum dose administered was 7.0 mg/kg/dose. There were no statistically significant differences in the occurrence of adverse neurologic events during therapy among subjects treated with oseltamivir versus those treated with the adamantanes (P = 0.13).
This is the largest report to date of oseltamivir use in children less than 12 months of age. Neurologic events were not more common with use of oseltamivir compared with that of the adamantanes. Dosing of oseltamivir was variable, illustrating the need for pharmacokinetic data in this younger population.
PMCID: PMC3703844  PMID: 19949363
oseltamivir; neuraminidase inhibitor; antiviral; children; infant; adamantanes; safety
5.  Fluconazole Loading Dose Pharmacokinetics and Safety in Infants 
PMCID: PMC3078721  PMID: 21085048
candidiasis; fluconazole; infant; neonate; pharmacology
6.  Exogenous estrogen does not attenuate the association between rofecoxib and myocardial infarction in perimenopausal women 
Rofecoxib has been proposed to increase the risk of myocardial infarction (MI) through suppression of cyclooxygenase (COX)-2 mediated prostacyclin. Estrogen may have protective effects through augmenting COX-2 expression and subsequently increasing prostacyclin. Estrogen may attenuate the association between rofecoxib and MI. We used 1999–2002 Medicaid claims data to measure the MI-hazard ratio (HR) attributed to rofecoxib exposure in estrogen exposed and unexposed 45–65 year old women. We identified 184,169 female rofecoxib users who contributed 309,504 person-years and experienced 1217 first MIs. Estrogen exposure appeared protective (MI-HR 0.72, 95% CI 0.62–0.84) in this cohort. Rofecoxib was associated with an elevated MI-HR in both estrogen exposed (2.01, 95% CI 1.60–2.54) and estrogen unexposed women (1.69, 95% CI 1.43–1.99). The rofecoxib-estrogen interaction ratio was not significantly different from 1 (1.19, 95% CI 0.91–1.57). Although estrogen use was associated with a lower risk of MI, it did not appear to attenuate the association between rofecoxib and MI.
PMCID: PMC3080455  PMID: 21052013
myocardial infarction; hormone replacement therapy; pharmacoepidemiology; cyclooxygenase inhibitor
7.  Fluconazole Dosing for the Prevention or Treatment of Invasive Candidiasis in Young Infants 
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.
Our population PK 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 population’s pharmacokinetic response to fluconazole to predict fluconazole exposure (median, 10th and 90th percentile population variability range) after 3, 6 and 12 mg/kg dosing.
For the treatment of invasive candidiasis, a dose of at least 12 mg/kg/day in the 1st 90 days after birth is needed to achieve an AUC of >400 mg*h/L and an AUC/MIC>50 for Candida species with MIC<8 µg/ml in ≥ 90% of <30 week gestation infants and 80% of 30–40 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 23–29 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 µg/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.
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.
PMCID: PMC2771384  PMID: 19593252
neonate; pharmacology; antifungal treatment
8.  Daptomycin Use in Infants: Report of Two Cases with Peak and Trough Drug Concentrations 
We report two infants treated with daptomycin for methicillin-resistant Staphylococcus aureus infection and describe peak and trough blood concentrations measured during therapy. The peak concentrations were 41.7 mcg/ml and 36.7 mcg/ml, and the 12-hour trough concentrations were 12.7 mcg/ml and 16.3 mcg/ml, respectively. Even though the infants received higher doses than adults, their drug concentrations were comparable to those observed in adults treated with regular dosing of daptomycin.
PMCID: PMC2752140  PMID: 18309318
Staphylococcus aureus; neonates; daptomycin; premature; drug concentration
9.  Gene Induction during Differentiation of Human Pulmonary Type II Cells In Vitro 
Mature alveolar type II cells that produce pulmonary surfactant are essential for adaptation to extrauterine life. We profiled gene expression in human fetal lung epithelial cells cultured in serum-free medium containing dexamethasone and cyclic AMP, a treatment that induces differentiation of type II cells. Microarray analysis identified 388 genes that were induced > 1.5-fold by 72 h of hormone treatment. Induced genes represented all categories of molecular function and subcellular location, with increased frequency in the categories of ionic channel, cell adhesion, surface film, lysosome, extracellular matrix, and basement membrane. In time-course experiments, self-organizing map analysis identified a cluster of 17 genes that were slowly but highly induced (5- to ∼ 190-fold) and represented four functional categories: surfactant-related (SFTPC, SFTPA, PGC, SFTPB, LAMP3, LPL), regulatory (WIF2, IGF2, IL1RL1, NR4A2, HIF3A), metabolic (MAOA, ADH1B, SEPP1), and transport (SCNN1A, CLDN18, AQP4). Induction of both mRNA and protein for these genes, which included nine newly identified regulated genes, was confirmed, and cellular localization was determined in both fetal and postnatal tissue. Induction of lysosomal-associated membrane protein 3 required both hormones, and expression was localized to limiting membranes of lamellar bodies. Hormone-induced differentiation of human type II cells is associated with genome-wide increased expression of genes with diverse functions.
PMCID: PMC2644235  PMID: 16474099
cyclic AMP; epithelial differentiation; glucocorticoid; human fetal lung; type II cell

Results 1-9 (9)