P B Smith

Early and late onset sepsis in very-low-birth-weight infants from a large group of neonatal intensive care units.

BACKGROUND Very-low-birth-weight (VLBW, <1500 g birth weight) infants are at high risk for both early- and late-onset sepsis. Prior studies have observed a predominance of Gram-negative organisms as a cause of early-onset sepsis and Gram-positive organisms as a cause of late-onset sepsis. These reports are limited to large, academic neonatal intensive care units (NICUs) and may not reflect findings in other units. The purpose of this study was to determine the risk factors for sepsis, the causative organisms, and mortality following infection in a large and diverse sample of NICUs. METHODS We analysed the results of all cultures obtained from VLBW infants admitted to 313 NICUs from 1997 to 2010. RESULTS Over 108,000 VLBW infants were admitted during the study period. Early-onset sepsis occurred in 1032 infants, and late-onset sepsis occurred in 12,204 infants. Gram-negative organisms were the most commonly isolated pathogens in early-onset sepsis, and Gram-positive organisms were most commonly isolated in late-onset sepsis. Early- and late-onset sepsis were associated with increased risk of death controlling for other confounders (odds ratio 1.45 [95% confidence interval [CI] 1.21,1.73], and OR 1.30 [95%CI 1.21, 1.40], respectively). CONCLUSIONS This is the largest report of sepsis in VLBW infants to date. Incidence for early-onset sepsis and late-onset sepsis has changed little over this 14-year period, and overall mortality in VLBW infants with early- and late-onset sepsis is higher than in infants with negative cultures.

Safety and Pharmacokinetics of Repeat-Dose Micafungin in Young Infants

Given the risk of central nervous system infection, relatively high weight‐based echinocandin dosages may be required for the successful treatment of invasive candidiasis and candidemia in young infants. This open‐label study assessed the safety and pharmacokinetics (PK) of micafungin in 13 young infants (>48 h and <120 days of life) with suspected candidemia or invasive candidiasis. Infants of body weight ≥1,000 and <1,000 g received 7 and 10 mg/kg/day, respectively, for a minimum of 4–5 days. In the 7‐mg/kg/day group, the mean baseline weight and gestational age were 2,101 g and 30 weeks, respectively; in the 10‐mg/kg/day group, they were 688 g and 25 weeks, respectively. The median pharmacokinetic values for the 7‐ and 10‐mg/kg/day groups, respectively, were as follows: area under the concentration–time curve from 0 to 24 h (AUC0–24), 258.1 and 291.2 µg·h/ml; clearance at steady state adjusted for body weight, 0.45 and 0.57 ml/min/kg; maximum plasma concentration, 23.3 and 24.9 µ g/ml; and volume of distribution at steady state adjusted for body weight, 341.4 and 542.8 ml/kg. No deaths or discontinuations from treatment occurred. These data suggest that micafungin dosages of 7 and 10 mg/kg/day are well tolerated and provide exposure levels that have been shown (in animal models) to be adequate for central nervous system coverage.

Population Pharmacokinetics of Micafungin in Neonates and Young Infants

ABSTRACT Micafungin is an echinocandin with potent activity against Candida spp. Hematogenous Candida meningoencephalitis (HCME) is a frequent complication of disseminated Candida infection in premature infants. A preclinical model of HCME suggests that micafungin may be an effective agent for this syndrome, but relatively high weight-based dosages are required. This prompted the further study of the safety and pharmacokinetics (PK) of micafungin in infants. Here, we describe the population pharmacokinetics of micafungin in 47 infants with a proven or presumptive diagnosis of disseminated candidiasis, who received 0.75, 1.5, 3, 7, 10, and 15 mg/kg of micafungin. The drug was infused daily, and samples were taken in the first dosing interval and at steady state. Serum concentrations were measured using high-performance liquid chromatography (HPLC). Data were modeled using an allometric pharmacokinetic model using a three-fourths scaling exponent for clearance and parameters normalized to a 70-kg adult. Drug exposures were estimated using Monte Carlo simulation. Optimal sampling times were determined using D-optimal design theory. The fit of the allometric model to the data was highly acceptable. The pharmacokinetics of micafungin were linear. The weight-normalized estimates of clearance and volume of distribution approximated those previously described for adults. The original population parameter values could be recapitulated in the Monte Carlo simulations. A dosage of 10 mg/kg/day resulted in 82.6% of patients with areas under the concentration-time curve (AUCs) that are associated with near-maximal decline in fungal burden within the central nervous system (CNS).

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.

Long-term morbidities associated with vocal cord paralysis after surgical closure of a patent ductus arteriosus in extremely low birth weight infants

Objective:Determine associations between left vocal cord paralysis (LVCP) and poor respiratory, feeding and/or developmental outcomes in extremely low birth weight (ELBW) infants following surgical closure of a patent ductus arteriosus (PDA).Study Design:ELBW infants who underwent PDA ligation between January 2004 and December 2006 were identified. We compared infants with and without LVCP following ligation to determine relationships between LVCP and respiratory morbidities, feeding and growth difficulties and neurodevelopmental impairment at 18 to 22-month follow-up. Students t-test, Fishers exact test and multivariable regression analyses were used to determine associations.Result:In all, 60 ELBW infants with a mean gestational age of 25 weeks and mean birth weight of 725 g had a PDA surgically closed. Twenty-two of 55 survivors (40%) were diagnosed with LVCP post-operatively. Infants with LVCP were significantly more likely to develop bronchopulmonary dysplasia (82 vs 39%, P=0.002), reactive airway disease (86 vs 33%, P<0.0001), or need for gastrostomy tube (63 vs 6%, P<0.0001).Conclusion:LVCP as a complication of surgical ductal ligation in ELBW infants is associated with persistent respiratory and feeding problems. Direct laryngoscopy should be considered for all infants who experience persistent respiratory and/or feeding difficulties following PDA ligation.

Characteristics of patients who die of necrotizing enterocolitis.

Objective:Necrotizing enterocolitis (NEC) is associated with high morbidity and mortality among infants admitted for intensive care. The factors associated with mortality and catastrophic presentation remain poorly understood. Our objective was to describe the factors associated with mortality in infants with NEC and to quantify the degree to which catastrophic presentation contributes to mortality in infants with NEC. Catastrophic NEC was defined before data analysis as NEC that led to death within 7 days of diagnosis.Study Design:We performed a retrospective review of the Pediatrixs Clinical Data Warehouse (1997 to 2009, n=560,227) to compare the demographic, therapeutic and outcome characteristics of infants who survived NEC vs those who died. Associations were tested by bivariate and multivariate analysis.Result:We compared the 5594 infants diagnosed with NEC and who were discharged home with 1505 infants diagnosed with NEC who died. In multivariate analysis, the factors associated with death (P<0.01 in analysis) were lower estimated gestational age, lower birth weight, treatment with assisted ventilation on the day of diagnosis of NEC, treatment with vasopressors at the time of diagnosis, and Black race. Patients who received only ampicillin and gentamicin on the day of diagnosis were less likely to die. Two-thirds of NEC deaths occurred quickly (<7 days from diagnosis), with a median time of death of one day from time of diagnosis. Infants who died within 7 days of diagnosis had a higher birth weight, more often were on vasopressors and high frequency ventilation at the time of diagnosis compared with patients who died at 7 or more days. Although mortality decreased with increasing gestational age, the proportion of deaths that occurred within 7 days was relatively consistent (65 to 75% of the patients who died) across all gestational ages.Conclusion:Mortality among infants who have NEC remains high and infants who die of NEC commonly (66%) die quickly. Most of the factors associated with mortality are related to immaturity, low birth weight and severity of illness.

Innovative clinical trial design for pediatric therapeutics

Until approximately 15 years ago, sponsors rarely included children in the development of therapeutics. US and European legislation has resulted in an increase in the number of pediatric trials and specific label changes and dosing recommendations, although infants remain an understudied group. The lack of clinical trials in children is partly due to specific challenges in conducting trials in this patient population. Therapeutics in special populations, including premature infants, obese children and children receiving extracorporeal life support, are even less studied. National research networks in Europe and the USA are beginning to address some of the gaps in pediatric therapeutics using novel clinical trial designs. Recent innovations in pediatric clinical trial design, including sparse and scavenged sampling, population pharmacokinetic analyses and ‘opportunistic’ studies, have addressed some of the historical challenges associated with clinical trials in children.

A systematic review of randomized controlled trials for the prevention of bronchopulmonary dysplasia in infants

Objective:Bronchopulmonary dysplasia (BPD) is the most common cause of pulmonary morbidity in premature infants and is associated with life-long morbidities. Developing drugs for the prevention of BPD would improve public health. We sought to determine characteristics of favorable randomized controlled trials (RCTs) of drugs for BPD prevention.Study Design:We searched MEDLINE and EMBASE from 1992 to 2014 using the MeSH terms ‘BPD’ and ‘respiratory distress syndrome, newborn’. We included a Cochrane Library search to ensure inclusion of all available RCTs. We identified RCTs with BPD as a primary or secondary outcome and determined the definition of BPD used by the study. We determined whether a phase I or phase II study—to determine drug safety, efficacy or optimal dose—was performed before the RCT. Finally, we searched the Cochrane Library for meta-analyses for each drug and used the results of available meta-analyses to define a favorable versus unfavorable RCT.Result:We identified 2026 articles; 47 RCTs met our inclusion criteria encompassing 21 drugs; 5 of the drugs reduced the incidence of BPD. We found data from phase I or II studies for 16 of the drugs, but only 1 demonstrated a reduction of BPD.Conclusion:The majority of the drugs studied in RCTs failed to reduce the incidence of BPD. Performing early-phase studies before phase III trials might provide necessary information on drugs and drug doses capable of preventing BPD, thus informing the development of future RCTs.

Adaptation of a Postoperative Handoff Communication Process for Children With Heart Disease A Quantitative Study

Handoff communication is a point of vulnerability when valuable patient information can be inaccurate or omitted. An institutional protocol was implemented in 2005 to improve the handoff from the operating room to the intensive care unit after pediatric cardiac surgery. A cross-sectional study of the present process was performed to understand how users adapt a communication intervention over time. Twenty-nine handoff events were observed. Individuals required for the handoff were present at 97% of the events. Content items averaged a 53% reporting rate. Some clinical information not specified in the protocol demonstrated a higher reporting rate, such as echocardiogram results (68%) and vascular access (79%). A mean of 2.3 environmental distractions per minute of communication were noted. Participant-directed adjustments in content reporting suggest that a facilitator in process improvement is user-centered innovation. Future handoff communication interventions should reduce nonessential distractions and incorporate a discussion of the anticipated patient course.

Safety and Pharmacokinetics of Multiple-Dose Anidulafungin in Infants and Neonates

Candida infections are common and often fatal in infants and neonates. Anidulafungin has excellent activity against Candida species, but the pharmacokinetics (PK) and safety of the drug in infants and neonates are unknown. The object of our study was to determine the PK and safety of anidulafungin in infants and neonates at risk for invasive candidiasis. Intravenous anidulafungin (1.5 mg/kg/day maintenance dose) was administered to 15 infants and neonates over 3 to 5 days. Plasma samples were collected after the first dose and again after the third to fifth doses. The pharmacokinetic parameters of the drug were determined by noncompartmental analysis. Safety was assessed using National Cancer Institute common toxicity criteria. The study showed that drug exposure levels were similar between neonates and infants; the median areas under the concentration–time curve (range) was 75 (30–109) µg·h/ml and 98 (55–278) µg·h/ml (P = 0.12) for neonates and infants, respectively. No drug‐related serious adverse events were observed. The study results indicate that neonates and infants receiving 1.5 mg/kg/day have anidulafungin exposure levels similar to those in children receiving similar weight‐based dosing and in adult patients receiving 100 mg/day.