Preterm birth is increasing worldwide, and late preterm births, which comprise more than 70% of all preterm births, account for much of the increase. Early and late onset sepsis results in significant mortality in extremely preterm infants, but little is known about sepsis outcomes in late preterm infants.
This is an observational cohort study of infants < 121 days of age (119,130 infants less than or equal to 3 days of life and 106,142 infants between 4 and 120 days of life) with estimated gestational age at birth between 34 and 36 weeks, admitted to 248 neonatal intensive care units in the United States between 1996 and 2007.
During the study period, the cumulative incidence of early and late onset sepsis was 4.42 and 6.30 episodes per 1000 admissions, respectively. Gram-positive organisms caused the majority of early and late onset sepsis episodes. Infants with early onset sepsis caused by Gram-negative rods and infants with late onset sepsis were more likely to die than their peers with sterile blood cultures (OR 4.39, 95% CI 1.71–11.23, P=0.002; and OR 3.37, 95% CI 2.35–4.84, P<0.001, respectively).
Late preterm infants demonstrate specific infection rates, pathogen distribution, and mortality associated with early and late onset sepsis. The results of this study are generalizable to late preterm infants admitted to the special care nursery or neonatal intensive care unit.
blood culture; neonate; prematurity; infection; near term
Describe cerebrospinal fluid parameters in infants with culture-proven Group B streptococcal meningitis in the era of intrapartum antibiotic prophylaxis.
Cohort study of the first lumbar puncture from 13,495 infants cared for at 150 neonatal intensive care units. We compared cerebrospinal fluid parameters [white blood cell count, red blood cell count, glucose, and protein], demographics, and outcomes between infants with and without Group B streptococcal meningitis.
We identified 46 infants with Group B streptococcal meningitis. The median cerebrospinal fluid white blood cell count was 271 cells/mm3 for infants with Group B streptococcal meningitis and 6 cells/mm3 for infants without meningitis (p=0.0001). Of the infants with Group B streptococcal meningitis, 9/46 (20%) had negative blood cultures. Meningitis complicated 22/145 (15%) of episodes of early onset Group B streptococcal sepsis and 13/23 (57%) of episodes of late onset Group B streptococcal sepsis.
Group B streptococcal meningitis occurs in the presence of negative blood cultures. In hospitalized infants who undergo a lumbar puncture, Group B streptococcal sepsis is frequently complicated by GBS meningitis.
Group B streptococcus; intrapartum antibiotic prophylaxis; meningitis
The World Health Organization (WHO) has recommended the use of clinical staging alone and with total lymphocyte count to identify HIV infected children in need of antiretroviral therapy (ART) in resource-limited settings, when CD4 cell count is not available.
We prospectively enrolled children obtaining care for HIV infection at the Kilimanjaro Christian Medical Centre Pediatric Infectious Diseases Clinic in Moshi, Tanzania between March 2004 and May 2006 for this cohort study.
192 (89.7%) of 214 children met WHO ART initiation criteria based on clinical staging or CD4 cell count. Several low-cost measures identified individuals who met WHO ART initiation criteria to the following degree: WHO stages 3 or 4 had 87.5% (95% CI; 82.8 – 92.1) sensitivity and, by definition, 100% (CI; 100 – 100) specificity; WHO recommended advance disease TLC cutoffs: sensitivity = 23.9% (95% CI; 17.3 – 30.5) specificity = 78.2% (95% CI: 67.3 – 89.1). Low TLC was a common finding, (50/214; 23%); however, it did not improve the sensitivity or specificity of clinical staging in identifying the severely immunosuppressed stage 2 children. Growth failure or use of total lymphocyte counts in isolation were not reliable indicators of severe immunosuppression or need to initiate ART.
The use of total lymphocyte count does not improve the ability to identify children in need of ART compared to clinical staging alone. Low absolute lymphocyte count did not correlate with severe immunosuppression based on CD4 cell count in this cohort.
HIV/AIDS; ART; TLC; pediatrics; immunosuppression; CD4
The impact of early surgery on mortality in patients with native valve endocarditis (NVE) is unresolved. This study seeks to evaluate valve surgery compared to medical therapy for NVE, and to identify characteristics of patients who are most likely to benefit from early surgery.
Methods and Results
Using a prospective, multinational cohort of patients with definite NVE, the effect of early surgery on in-hospital mortality was assessed using propensity-based matching adjusting for survivor bias, and instrumental variable analysis. Patients were stratified by propensity quintile, paravalvular complications, valve perforation, systemic embolization, stroke, Staphylococcus aureus infection and congestive heart failure.
Of the 1552 patients with NVE, 720 (46%) underwent early surgery and 832 (54%) were treated with medical therapy. Compared to medical therapy, early surgery was associated with a significant reduction in mortality in the overall cohort (12.1% [87/720] vs. 20.7% [172/832]) and after propensity-based matching and adjustment for survivor bias (absolute risk reduction (ARR) = -5.9 %; p<0.001). Using a combined instrument, the instrumental variable adjusted ARR in mortality associated with early surgery was -11.2% (p<0.001). In sub-group analysis, surgery was found to confer a survival benefit compared to medical therapy among patients with a higher propensity for surgery (ARR= -10.9% for quintiles 4 and 5; p=0.002); those with paravalvular complications (ARR= -17.3 %; p<0.001), systemic embolization (ARR= -12.9%; p=0.002), S aureus NVE (ARR= -20.1%; p<0.001) and stroke (ARR= -13%; p=0.02) but not with valve perforation or congestive heart failure.
Early surgery for NVE is associated with an in-hospital mortality benefit compared to medical therapy alone.
early surgery; infective endocarditis; medical therapy; in hospital mortality
invasive candidiasis; amphotericin B deoxycholate; flucytosine; fluconazole; voriconazole; posaconazole; micafungin; anidulafungin; caspofungin
Treatment of Mycoplasma hominis meningitis in infants is limited by a lack of consensus regarding therapy and limited pharmacokinetic data for agents to which M. hominis is susceptible. We report the successful treatment of a premature infant with M. hominis meningitis with doxycycline and moxifloxacin and provide a pharmacokinetic profile of moxifloxacin.
meningitis; moxifloxacin; Mycoplasma hominis; infant; pharmacokinetic
Late-onset sepsis in premature infants is a major cause of morbidity, mortality, and increased medical costs. Risk factors include low birth weight, low gestational age, previous antimicrobial exposure, poor hand hygiene, and central venous catheters. Methods studied to prevent late-onset sepsis include early feedings, immune globulin administration, prophylactic antimicrobial administration, and improved hand hygiene. In this review, we will outline the risk factors for development of late-onset sepsis and evidence supporting methods for prevention of late-onset sepsis in premature infants.
This method provides a simple extraction procedure, as well as a validated, sensitive, and specific liquid chromatography-tandem mass spectrometry assay for the simultaneous quantification of ampicillin, piperacillin, tazobactam, meropenem, acyclovir, and metronidazole in human plasma. The method was validated over concentration ranges specific for each compound, with a lower limit of quantification of 50–300 ng/mL and a sample volume of 50 μL. The method is accurate and precise, with within- and between-day accuracy ranging from 85–110% and 92–110%, respectively, and within- and between-day precision of 89–111% and 91–109%, respectively. Simplicity, low plasma volume, and high throughput make this method suitable for clinical pharmacokinetic studies in premature infants.
prematurity; neonates; antibiotics; antivirals; HPLC; mass spectrometry
Children with short bowel syndrome requiring long-term total parenteral nutrition are at high risk for catheter-associated infections. The optimal management of catheter infections in this patient population is unknown. We conducted a retrospective observational study in children with short bowel syndrome to compare outcomes of catheter-associated infections treated with catheter removal plus antibiotic therapy versus antibiotic therapy alone.
short gut; children; line infection
Invasive candidiasis (IC) is common and often fatal in extremely premature neonates. In the last decade, the therapeutic armamentarium for IC has markedly expanded; however, the pharmacokinetics, safety and efficacy of most antifungal agents in premature neonates are unknown. We will review the major systemic antifungal agents in clinical use.
Pharmacokinetic (PK) studies in preterm infants are rarely conducted due to the research challenges posed by this population. To overcome these challenges, minimal-risk methods such as scavenged sampling can be used to evaluate the PK of commonly used drugs in this population. We evaluated the population PK of metronidazole using targeted sparse sampling and scavenged samples from infants that were ≤32 weeks of gestational age at birth and <120 postnatal days. A 5-center study was performed. A population PK model using nonlinear mixed-effect modeling (NONMEM) was developed. Covariate effects were evaluated based on estimated precision and clinical significance. Using the individual Bayesian PK estimates from the final population PK model and the dosing regimen used for each subject, the proportion of subjects achieving the therapeutic target of trough concentrations >8 mg/liter was calculated. Monte Carlo simulations were performed to evaluate the adequacy of different dosing recommendations per gestational age group. Thirty-two preterm infants were enrolled: the median (range) gestational age at birth was 27 (22 to 32) weeks, postnatal age was 41 (0 to 97) days, postmenstrual age (PMA) was 32 (24 to 43) weeks, and weight was 1,495 (678 to 3,850) g. The final PK data set contained 116 samples; 104/116 (90%) were scavenged from discarded clinical specimens. Metronidazole population PK was best described by a 1-compartment model. The population mean clearance (CL; liter/h) was determined as 0.0397 × (weight/1.5) × (PMA/32)2.49 using a volume of distribution (V) (liter) of 1.07 × (weight/1.5). The relative standard errors around parameter estimates ranged between 11% and 30%. On average, metronidazole concentrations in scavenged samples were 30% lower than those measured in scheduled blood draws. The majority of infants (>70%) met predefined pharmacodynamic efficacy targets. A new, simplified, postmenstrual-age-based dosing regimen is recommended for this population. Minimal-risk methods such as scavenged PK sampling provided meaningful information related to development of metronidazole PK models and dosing recommendations.
Invasive fungal infections in immunocompromised children are common and often fatal. The first antifungal agents such as amphotericin B and fluconazole offered effective treatment, but their use was often limited by toxicity and resistance. Numerous new antifungal agents have since been developed and appear to be as effective. Most dosing and safety trials have been done in adults, and extrapolation of this data to children has proven inadequate. We reviewed the literature regarding the pharmacokinetics/pharmacodynamics (PK/PD) and safety of antifungal agents with an emphasis on the newer azoles and echinocandins. From a small but growing number of PK/PD trials, better dosing guidelines have been developed.
antifungal agents; pharmacology; pharmacokinetics; neonates; infants; children
Cardiovascular disease in children is common and results in significant morbidity and mortality. The sickest children with cardiovascular disease may require support with extracorporeal membrane oxygenation (ECMO) which provides life-saving assistance for children with refractory cardiorespiratory failure. Many classes of cardiovascular drugs are used in children, but very few of these agents have been well studied in children. The knowledge gap is even more pronounced in children supported with ECMO. Pharmacokinetic (PK) data collected to date (primarily from antibiotics and sedatives) suggest that the ECMO circuit has the potential to significantly alter the pharmacokinetics of drugs including changes in clearance and volume of distribution. Of all cardiovascular drugs administered to children supported by ECMO, only 11 have been partially studied and reported in the medical literature. Esmolol, amiodarone, nesiritide, bumetanide, sildenafil, and prostaglandin E1 appear to require dosing modifications in children supported by ECMO, while it appears that hydralazine, nicardipine, furosemide, epinephrine, and dopamine can be dosed similarly to children not supported by ECMO. However, trials evaluating the PK of these drugs in patients supported by ECMO are extremely limited (i.e. case reports) and therefore definitive dosing recommendations are not plausible. Research efforts should focus on evaluating the PK of drugs in patients on ECMO in order to avoid therapeutic failures or unnecessary toxicities.
cardiovascular agents; extracorporeal membrane oxygenation; pharmacology; pharmacokinetics
Hematogenous Candida meningoencephalitis (HCME) is a serious infection in premature neonates. Anidulafungin is an echinocandin antifungal agent with potent activity against Candida spp., but its efficacy and optimal regimens for human neonates with HCME are not known. A well-validated rabbit model of HCME was used to define pharmacokinetic-pharmacodynamic (PK-PD) relationships of anidulafungin. A mathematical model was fitted to the entire data set. The experimental data were bridged to humans. A population PK model was fitted to the data from human neonates receiving anidulafungin receiving a loading dose of 3 mg/kg, followed by 1.5 mg/kg/day. Monte Carlo simulations were performed to identify candidate anidulafungin regimens for humans. All untreated rabbits succumbed by ≤96 h postinoculation. The PK of anidulafungin was linear with dose-dependent penetration into the cerebrum. Anidulafungin exerted a rapid antifungal effect that was apparent in the first dosing interval. Near-maximal antifungal activity was observed with dosages of 10 to 20 mg/kg/day. The bridging studies suggested that the current regimen of first 3 mg/kg, followed by 1.5 mg/kg/day, is suboptimal. Higher dosages were associated with progressively greater antifungal effect. Anidulafungin is effective for the treatment of experimental HCME. Higher dosages than those currently used for clinical care are required for maximal antifungal effect.
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.
clinical trial simulation; opportunistic study; pediatrics; pharmacodynamics; pharmacokinetics; pharmacometrics; therapeutics
Coagulase-negative staphylococci (CoNS) are the most commonly isolated pathogens in the neonatal intensive care unit (NICU). CoNS infections are associated with increased morbidity including neurodevelopmental impairment.
Describe the epidemiology of CoNS infections in the NICU. Determine mortality among infants with definite, probable, or possible CoNS infections.
We performed a retrospective cohort study of all blood, urine, and cerebrospinal fluid cultures from infants <121 postnatal days.
248 NICUs managed by the Pediatrix Medical Group from 1997 to 2009.
We identified 16,629 infants with 17,624 episodes of CoNS infection: 1734 (10%) definite, 3093 (17%) probable, and 12,797 (73%) possible infections. Infants with lower gestational age and birth weight had a higher incidence of CoNS infection. Controlling for gestational age, birth weight, and 5-minute Apgar score, infants with definite, probable, or possible CoNS infection had lower mortality—OR=0.74 (95% confidence interval; 0.61, 0.89), OR= 0.68 (0.59, 0.79), and OR=0.69 (0.63, 0.76)—compared to infants with negative cultures (P<0.001). No significant difference in overall mortality was found in infants with definite CoNS infection compared to those with probable or possible CoNS infection—OR=0.93 (0.75, 1.16) and OR=0.85 (0.70, 1.03), respectively.
CoNS infection was strongly related to lower gestational age and birth weight. Infants with clinical sepsis and culture-positive CoNS infection had lower mortality rates than infants with clinical sepsis and negative blood culture results. No difference in mortality between infants diagnosed with definite, probable, or possible CoNS infection was observed.
nosocomial infection; infant; prematurity; Staphylococcus
candidiasis; fluconazole; infant; neonate; pharmacology
Micafungin, a new echinocandin antifungal agent, has been widely used for the treatment of various fungal infections in human populations. Micafungin is predominantly cleared by biliary excretion and it binds extensively to plasma proteins (>99.5%). Micafungin body weight-adjusted clearance is higher in neonates than in adults, but the mechanisms underlying this difference are not understood. Previous work had revealed the roles of sinusoidal uptake (Na+-taurocholate co-transporting peptide, NTCP; organic anion transporting polypeptide, OATP) as well as canalicular efflux (bile salt export pump, BSEP; breast cancer resistance protein, BCRP) transporters in micafungin hepatobiliary elimination. In the present study, the relative protein expression of hepatic transporters was compared between liver homogenates from neonates and adults. Also, the extent of micafungin binding to serum from neonates and adults was measured in vitro. The results indicate that relative expression levels of NTCP, OATP1B1/3, BSEP, BCRP, and MRP3 were similar in neonates and in adults. However, micafungin fraction unbound (fu) in neonatal serum was about 8-fold higher than in adult serum (0.033 ± 0.012 versus 0.004 ± 0.001, respectively). While there was no evidence for different intrinsic hepatobiliary clearance of micafungin between neonates and adults, our data suggest that age-dependent serum protein binding of micafungin is responsible for its higher clearance in neonates compared to adults.
micafungin; pediatric drug disposition; serum binding; clearance prediction; antifungal
The impact of age and weight on outcomes following the Fontan operation is unclear. Previous analyses have suggested that lower weight-for-age z-score is an important predictor of poor outcome in patients undergoing bidirectional Glenn. We evaluated variation in age, weight, and weight-for-age z-score at Fontan across institutions, and the impact of these variables on post-operative morbidity and mortality.
Patients in the Society of Thoracic Surgeons Congenital Heart Surgery Database undergoing the Fontan operation (2000–2009) were included. Center variation in age, weight, and weight-for-age z-score were described. Multivariable analysis was performed to evaluate the impact of age, weight, and weight-for-age z-score on in-hospital mortality, Fontan failure (combined in-hospital mortality and Fontan takedown/revision), post-operative length of stay, and complications, adjusting for other patient and center factors.
A total of 2747 patients (68 centers) were included: 61% male; 45% right dominant lesions (38% left dominant, 17% undifferentiated). An extracardiac conduit Fontan (vs. lateral tunnel) was performed in 63%; 65% were fenestrated. Median age and weight at Fontan operation and proportion with weight-for-age z-score <−2 varied across centers ranging from 1.7–4.8 yrs, 10.5–16.1 kg, and 0%–30%, respectively. In multivariable analysis, age and weight were not significantly associated with outcome. Weight-for-age z-score <−2 was associated with increased in-hospital mortality (OR 2.73, 95%CI 1.09–6.86), Fontan failure (OR 2.59, 95%CI 1.24–5.40), and longer length of stay (+1.2 days, 95%CI 0.1–2.4).
Weight-for-age z-score <−2 is associated with significant morbidity and mortality following the Fontan operation independent of other patient and center characteristics.
Congenital Heart Disease; Outcomes
Congress has authorized the U.S. Food and Drug Administration (FDA) to provide industry sponsors with a 6-month extension of drug marketing rights under the Pediatric Exclusivity Provision if FDA-requested pediatric drug trials are conducted. The cost and economic return of pediatric exclusivity to industry sponsors has been shown to be highly variable. We sought to determine the cost of performing pediatric exclusivity trials within a single therapeutic area and the subsequent economic return to industry sponsors.
We evaluated 9 orally administered anti-hypertensive drugs submitted to the FDA under the Pediatric Exclusivity Provision from 1997–2004 and obtained key elements of the clinical trial designs and operations. Estimates of the costs of performing the studies were generated and converted into after-tax cash outflow. Market sales were obtained and converted into after-tax inflows based on 6 months of additional patent protection. Net economic return and net return-to-cost ratios were determined for each drug.
Of the 9 anti-hypertensive agents studied, an average of 2 studies per drug was performed, including at least 1 pharmacokinetic study and a safety and efficacy study. The median cost of completing a pharmacokinetic trial was $862,000 (range: $556,000–1.8 million). The median cost of performing safety and efficacy trials for these agents was $4.3 million (range: $2.1 million–12.9 million). The ratio of net economic return to cost was 17 (range: 4–64.7).
We found that, within a cohort of anti-hypertensive drugs, the Pediatric Exclusivity Provision has generated highly variable, yet lucrative returns to industry sponsors.
clinical trials; hypertension; pediatrics; drugs; cost-benefit analysis
In pediatric cardiac surgery, infection is a leading cause of morbidity and mortality. We created a model to predict risk of major infection in this population.
Using the Society of Thoracic Surgeons Congenital Heart Surgery Database, we created a multivariable model in which the primary outcome was major infection (septicemia, mediastinitis, or endocarditis). Candidate independent variables included demographic characteristics, comorbid conditions, preoperative factors, and cardiac surgical procedures. We created a reduced model by backward selection and then created an integer scoring system using a scaling factor with scores corresponding to percent risk of infection.
Of 30,078 children from 48 centers, 2.8% had major infection (2.6% septicemia, 0.3% mediastinitis, and 0.09% endocarditis). Mortality and postoperative length of stay were greater in those with major infection (mortality: 22.2% vs. 3.0%; length of stay > 21 days: 69.9% vs. 10.7%). Young age, high complexity, previous cardiothoracic operation, preoperative length of stay >1 day, preoperative ventilator support, and presence of a genetic abnormality were associated with major infection after backward selection (p<0.001). Estimated infection risk ranged from <0.1% to 13.3%; the model discrimination was good (c-index 0.79).
We created a simple bedside tool to identify children at high risk for major infection after cardiac surgery. These patients may be targeted for interventions to reduce the risk of infection and for inclusion in future clinical trials.
Congenital heart disease; Infection; Outcomes
Purpose of review
Systemic infections in premature and term infants cause significant morbidity and mortality in spite of appropriate antimicrobial therapy. Consequently, immunotherapy has emerged as a potential adjuvant therapeutic modality to reduce the incidence and mortality associated with neonatal sepsis.
The most recent findings during the review period include systematic reviews of previously published trials evaluating the use of intravenous immunoglobulin and colony stimulating factors in neonatal sepsis. In addition, the most recent trials describing the use of anti-staphylococcal antibodies, probiotics, glutamine supplementation, recombinant human protein C, and lactoferrin in the prevention and treatment of neonatal sepsis have been reviewed.
Immunotherapy used as an adjuvant for the prevention and treatment of neonatal sepsis holds promise. Clinical trials specifically designed towards the neonatal population and appropriately powered to detect treatment differences are necessary prior to universal recommendation of these therapies in the nursery.
newborn; prematurity; systemic infection; immune system
We compared costs, length of stay, and mortality between adults with Candida albicans and Candida glabrata bloodstream infections. Early evidence of C glabrata, as defined by a positive culture within 2 days of admission, was associated with higher costs ($56026 vs $32810; P = .04) and longer hospital stays (19.7 vs 14.5 days; P = .05) compared with early evidence of C albicans. Mortality was similar between the groups.
Invasive Candida infections are a leading cause of mortality and morbidity in neonatal intensive care units (NICUs). Micafungin is a promising therapeutic option for treatment of invasive fungal infections in infants given its safety profile in older children and adults. Understanding micafungin safety in infants is particularly important because antifungals are most often used in premature infants with multiple underlying medical conditions in a critical care setting.
This article reviews the literature evaluating the safety profile of micafungin in infants and offers recommendations for optimal dosing for treatment of invasive candidiasis in the NICU setting. The review was performed using a Medline search in September 2010 for related articles from 1990 to present with the Mesh related terms ‘micafungin’ and ‘safety’ in combination with the free words ‘antifungal’, ‘candidiasis’, ‘drug toxicity’, ‘infant, premature’, and ‘infant, newborn’.
Despite the limitations of the existing literature, we believe micafungin dosing of 10 mg/kg/day for all term and preterm infants is a viable treatment option in the NICU setting for management of invasive candidiasis. Although the number of infants for whom safety data are reported is small, higher doses of micafungin appear safe and well-tolerated in this population.
adverse effects; drug toxicity; micafungin; premature infants