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Clinical research involving children and adolescents with obesity is challenging due to recruitment, transportation barriers, parents/guardians working multiple jobs and the need to coordinate the schedule of the participant and the parent/guardian. We describe recruitment efforts and successes for a longitudinal observational study of adolescents with obesity.

Background This study sought to assess the pharmacokinetic and pharmacodynamic relationships of caffeine citrate therapy in preterm neonates who had therapeutic drug monitoring (TDM) in the post-extubation period. Methods A retrospective observational study was conducted in preterm neonates who received caffeine citrate therapy for apnea of prematurity and had TDM done in the post-extubation period between January 2006 and October 2011. The relationships between pharmacodynamic effects (heart rate, respiratory rate, episodes of apnea, adverse events) and caffeine serum concentrations were explored. Results A total of 177 blood samples were obtained from 115 preterm neonates with a median (range) gestational age of 29 (24 – 33) weeks and birth weight of 1230 (607 – 2304) kg. Caffeine citrate therapy was initiated at a median (interquartile range) postnatal age of 1 (1 – 3) day and TDM was performed at a postnatal age of 15 (10 – 24) days. No direct correlations were found between respiratory rate or apneic episodes and caffeine serum concentrations; however, heart rate and caffeine serum concentrations were significantly correlated (p

Herbal medicines (HMs) have been well known to people of the European Union (EU) and Russia for centuries. Currently, Western HMs can be classified into two categories, plant-derived conventional medicines and dietary supplements. Interest to HMs has grown rapidly in all countries during the past two decades.The main goal of this review article is to present the history of HMs in the EU and Russia, forms of modern HMs, including Oriental Medicines that are popular among consumers of both countries. Additional discussion points comprise safety and adulteration issues associated with HMs, including regulatory changes and new legislative measures undertaken by the authorities. Materials available from legislative and governmental websites, PubMed and news media were used. Expert commentary: Due to cultural diversities in the EU and Russia, traditional HMs of other regions, particularly Chinese Traditional and Ayurvedic medicines, are also popular. Recently, dietary supplements containing multiple herbal and other natural products have flooded the EU and Russian markets. Pharmacovigilance in these markets is challenging in terms of establishing quality and safety of ingredients, determining efficacy, and defining risks of herb-herb and herb-drug interactions. Both the EU and Russia have introduced new legislation aimed to overcome these deficiencies.

Aim The study aims were to characterize risperidone and (±)-9-hydroxyrisperidone pharmacokinetic (PK) variability in children and adolescents and to evaluate covariate effects on PK parameters. Methods Steady-state samples were drawn at predose, 1, 2, 4, and 7 hours postdose; cytochrome P450 2D6 (CYP2D6) genotypes were available for 28 subjects. A nonlinear mixed-effects model (NONMEM) modeled the PKs of risperidone and (±)-9-hydroxyrisperidone; covariates included age, weight, sex, and CYP2D6 phenotype. The model included 497 observations [risperidone (n = 163), (+) and (-)-9-hydroxyrisperidone (n = 334)] from 45 subjects aged 3-18.3 (mean 9.6 ± 3.7) years, weighing 16.8-110 (43 ± 20.2) kg. Results A 1-compartment mixture model described risperidone and (±)-9-hydroxyrisperidone clearances for 3 CYP2D6 metabolizer subpopulations: extensive, intermediate, and poor. Weight significantly affected (±)-9-hydroxyrisperidone clearance. Clearance estimates in the mixture model were poor metabolizer 9.38 L/h, intermediate metabolizer 29.2 L/h, and extensive metabolizer 37.4 L/h. Conclusion Active moiety [risperidone plus (±)-9-hydroxyrisperidone] PK variability and the covariate effects were better explained with the addition of metabolite PK parameters. This model may aid the development of individualized risperidone dosing regimens in children and adolescents.

This review is the third installment in a comprehensive State of the Art series and aims to evaluate the use of fluoroquinolones in the management of P. aeruginosa infection in both children and adults with cystic fibrosis (CF). Oral and intravenous ciprofloxacin have been shown to be well-tolerated in the treatment of acute pulmonary exacerbations (APE) secondary to P. aeruginosa. Older literature supports an oral dosing regimen of 40 mg/kg/day divided every 12 hr, up to 2 g/day, and intravenous (IV) ciprofloxacin 30 mg/kg/day divided every 8 hr, maximum 1.2 g/day in children, and 750 mg administered orally twice a day or 400 mg IV every 8 hr in adults. However, a recent pharmacodynamic (PD) modeling study shows that the literature, U.S. Food and Drug Administration (FDA)-approved, and Cystic Fibrosis Foundation (CFF) guideline dosing regimens may be suboptimal for the treatment of P. aeruginosa in APE. Further study is warranted to determine if higher doses of ciprofloxacin are needed. Limited pharmacokinetic (PK), PK/PD, and efficacy studies involving levofloxacin exist in adult patients with CF. No pediatric data exists for levofloxacin in CF patients. Further study is needed to determine the tolerability and efficacy of levofloxacin in APE. At this time, the routine use of levofloxacin in the treatment of APE in pediatric and adult patients cannot be recommended.

Acute pulmonary exacerbations (APE) are well-described complications of cystic fibrosis (CF) and are associated with progressive morbidity and mortality. Despite aggressive management with two or more intravenous anti-pseudomonal agents, approximately 25% of exacerbations will result in a loss of lung function. The aim of this review is to provide an evidence-based summary of pharmacokinetic/pharmacodynamic (PK/PD), tolerability, and efficacy studies utilizing anti-pseudomonal cephalosporins (i.e., ceftazidime and cefepime) and penicillins (i.e., piperacillin–tazobactam and ticarcillin–clavulanate) in the treatment of APE and to identify areas where further study is warranted. The ceftazidime and cefepime dosing ranges from the literature are 200–400 mg/kg/day divided every 6–8 hr, maximum 8–12 g/day, and 150–200 mg/kg/day divided every 6–8 hr, up to 6–8 g/day, respectively. The literature supported dosing ranges for piperacillin and ticarcillin are 350–600 mg/kg/day divided every 4 hr, maximum 18–24 g/day of piperacillin component, and 400–750 mg/kg/day divided every 6 hr, up to 24–30 g/day of ticarcillin component, respectively. As a large portion of CF patients will not regain their lung function following an APE, we suggest the need to optimize antibiotic dosing and dosing regimens used to treat an APE in efforts to improve outcomes for CF patients infected with Pseudomonas aeruginosa. Future studies are needed to determine the clinical efficacy of higher than FDA-approved doses of ceftazidime, cefepime, and ticarcillin–clavulanate in APE. The usefulness of high dose piperacillin (>600 mg/kg/day) may be limited due to treatment-related adverse effects. Further understanding of these adverse effects in CF patients is needed. Pediatr Pulmonol. 2013; 48:107–122. © 2012 Wiley Periodicals, Inc.

Patients with cystic fibrosis (CF) often experience acute pulmonary exacerbations (APE) and may be treated with a wide variety of intravenous antibiotics. The aim of this review is to provide an evidence-based summary of pharmacokinetic/pharmacodynamic (PK/PD), tolerability, and efficacy studies utilizing the intravenous (IV) polymixin antibiotic colistimethate sodium (CMS) in the treatment of APE and to identify areas where further study is warranted. Currently, there is not an international standard on the labeling of CMS products. As a result, this has lead to confusion in the interpretation of the literature with respect to efficacy, tolerance, and optimal dosing strategy. The dosing ranges of IV CMS from the literature are 5.3-12.9 mg/kg/day, maximum 480 mg per day for 60 kg patient (Colomycin® injection-European product) and 8-21.3 mg/kg/day, maximum 800 mg per day for 60 kg patient (Coly-Mycin M® parenteral-US product).The literature supports a CMS dose of 8 mg/kg/day divided every 8 hr (maximum 480 mg/day) for the treatment of APE secondary to Pseudomonas aeruginosa. The maximum recommended CMS dose of 480 mg/day is less than is recommended by the FDA-approved and CFF dosing guidelines but in agreement with UK CF Trust Antibiotic Working Group recommendations. There is debate over the frequency of CMS administration (once daily vs. thrice-daily) and its impact on resistance and clinical efficacy. Further study is needed to determine the tolerability and efficacy of extended-interval dosing of CMS in the treatment of APE.

Population pharmacokinetic modelling is widely used within the field of clinical pharmacology as it helps to define the sources and correlates of pharmacokinetic variability in target patient populations and their impact upon drug disposition. This review focuses on the fundamentals of population pharmacokinetic modelling and provides an overview of the commonly available software programs that perform these functions. This review attempts to define the common, fundamental aspects of population pharmacokinetic modelling through a discussion of the literature describing the techniques and placing them in the appropriate context. An overview of the most commonly available software programs is also provided. Population pharmacokinetic modelling is a powerful approach where sources and correlates of pharmacokinetic variability can be identified in a target patient population receiving a pharmacological agent. There is a need to further standardize and establish the best approaches in modelling so that any model created can be systematically evaluated and the results relied upon. Various nonlinear mixed-effects modelling methods, packaged in a variety of software programs, are available today. When selecting population pharmacokinetic software programs, the consumer needs to consider several factors, including usability (e.g. user interface, native platform, price, input and output specificity, as well as intuitiveness), content (e.g. algorithms and data output) and support (e.g. technical and clinical).

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Despite its increased use, the pharmacokinetics (PK) of mycophenolic acid (MPA) and the relationship between dose, plasma concentration and exposure are poorly understood, especially in children. • The PK of MPA are associated with high inter- and intra-individual variability. • MPA and its metabolites, like the inactive 7-O-MPA-β-glucuronide (MPAG) undergo enterohepatic circulation (EHC), which can contribute to an increase in exposure to MPA of 40% (range 10–60%). WHAT THIS STUDY ADDS • Thisis the first report of MPA PK in adolescents with childhood-onset systemic lupus erythematosus (cSLE). • The proposed final population PK model successfully incorporates the physiological aspects associated with MPA disposition, which includes MPA and its main metabolite MPAG, and adequately reflects the complex processes of absorption and enterohepatic circulation associated with mycophenolate mofetil (MMF) oral dosing in patients with cSLE. • This model provides a basis for further development of a model-based Bayesian estimator for individualized MPA dosing in paediatric patients treated for cSLE. AIM This study aimed to develop a population pharmacokinetic (PK) enterohepatic recycling model for MPA in patients with childhood-onset systemic lupus erythematosus (cSLE). METHODS MPA concentration–time data were from outpatients on stable oral mycophenolate mofetil (MMF) and collected under fasting conditions, with standardized meals (1 and 4 h post-dose). Sampling times were pre-dose, 20, 40 min, 1, 1.5, 2, 3, 4, 6 and 9 h, post dose. The population PK analysis simultaneously modelled MPA and 7-O-MPA-β-glucuronide (MPAG) concentrations using nonlinear mixed effect modelling. RESULTS PK analysis included 186 MPA and MPAG concentrations (mg l–1) from 19 patients. cSLE patients, age range 10–28 years, median 16.5 years were included. Mean ± SD disease duration was 3.8 ± 3.7 years. The final PK model included a gallbladder compartment for enterohepatic recycling and bile release time related to meal times, with first order absorption and single series of transit compartments. The PK estimates for MPA were CL1/F 25.3 l h–1, V3/F 20.9 l, V4/F 234 l and CL2/F 19.8 l h–1. CONCLUSION The final model fitted the complex processes of absorption and enterohepatic circulation (EHC) in those treated with MMF for cSLE and could be applied in Bayesian dose optimization algorithms.

Background The Intermountain Cystic Fibrosis Pediatric Center utilizes ticarcillin-clavulanate 400 mg/kg/d divided every 6 hours, (maximum 24 g/d). This dosing strategy is higher than the Food and Drug Administration (FDA)–approved package labeling. We evaluated the microbiologic efficacy of this dosing regimen. Objectives The primary study objective was to predict the pharmacokinetic (PK) and pharmacodynamic (PD) MIC breakpoints (the highest MIC with a probability of target attainment [PTA] of at least 90%) for the bacteriostatic and bactericidal targets of ticarcillin activity against Pseudomonas aeruginosa using the study dosing regimen. A secondary objective was to evaluate the tolerability profile of the higher ticarcillin-clavulanate dosing regimen in children with cystic fibrosis (CF). Methods This was a population-based PK-PD modeling study of pediatric CF patients admitted from January 1, 2005 to December 31, 2009 who received the dosing regimen for at least 7 days. Population PK and PD models were used to estimate PK and PD parameters for 127 clinically evaluable patients. A 10,000-patient Monte Carlo simulation was performed to estimate the target time in which free drug concentrations exceeded the MIC of the infecting organism. The 2 PK-PD targets of microbiologic efficacy included ≥30% for bacteriostasis and ≥50% for bactericidal effects of ticarcillin-clavulanate at higher than FDA-approved doses. Results A total of 127 patients (age, 0–19 years) met inclusion criteria. Serum concentration levels were modeled in this patient population using published PK parameters with intermittent ticarcillin peak concentrations reaching 288 (93.4) mg/L. The model predicted the PTA of the MICs for P. aeruginosa with a near-maximal bactericidal PK-PD MIC breakpoint of 16 μg/mL and a bacteriostasis PK-PD MIC breakpoint of 32 μg/mL. Conclusions The results of our simulation suggest that in this select pediatric population, higher than FDA-approved doses of ticarcillin-clavulanate were effective in achieving bactericidal effects among pseudomonal isolates with MICs P. aeruginosa isolates with MICs >32 μg/mL. Additional studies are warranted to determine the clinical effectiveness of this dosing regimen.

Current prednisone dosing in the treatment of young patients with childhood-onset systemic lupus erythematosus (cSLE) is largely based on achieving balance between therapeutic efficacy and toxicity, with weight-based dosing a common clinical practice. Despite the widespread use of prednisone, few attempts have been made to improve its clinical dosing regimen, and response to prednisone therapy remains variable.The purpose of this study was to characterize the pharmacokinetic (PK) properties of prednisolone, the metabolite of the prodrug prednisone, in cSLE patients and explore the relationship between PK properties and cSLE disease activity.Blood samples were taken 1 hour before the morning prednisone dose and at 20, 40, 60, and 90 minutes, and 2, 3, 4, 6, and 9 hours from 8 patients (ages 12-28 years) after an 8-hour fast. The mean weight-adjusted daily prednisone dose, stable for at least 30 days pre-study, was 0.29 mg/kg/d. PK analysis of prednisolone was performed using noncompartmental analysis with WinNonlin. cSLE disease activity was measured using the British Isles Lupus Assessment Group index and Systemic Lupus Erythematosus Disease Activity Index.Mean total prednisolone AUC(0-9), prednisone CL/F at steady state, and half-life were 1094 (range, 467-2404) ng/h/mL, 11 (range, 6.7-13.7) L/hr, and 2.6 (range, 1.3-3.9) hours. Mean total prednisolone AUC(0-9) normalized to prednisone dose by weight was 4361 (range, 1136-9580) ng/h/mL/mg/kg. Mean total prednisolone C(max) normalized to prednisone dose by weight was 1097 (range, 301-2211) ng/mL/mg/kg at 1.84 (range, 0.48-4) hours (T(max)). Patients on prednisone had interindividual variability in prednisolone AUC(0-9) (61% CV) and dose-adjusted AUC(0-9) (58% CV).Interindividual variability in systemic exposure to prednisolone in cSLE patients was observed.

Objectives This study aimed to investigate intravenous infusions as used in the neonatal intensive care setting, to determine the effect of gentamicin dose (mg), gentamicin concentrations (mg/ml), flow rate (ml/h) and flush volume (ml) upon the length of infusion time. Methods Intravenous infusions were set up to simulate administration of gentamicin to neonates. Dextrose (10%, w/v) was administered as the primary intravenous fluid at 3.8 or 18.7 ml/h. Gentamicin doses (0.5 mg/0.2 ml, 2 mg/0.2 ml, 2.5 mg/1.0 ml, or 10 mg/1.0 ml) were delivered into the intravenous line at a T-connection using a Graseby pump over 35 min. This was followed by a saline flush of 1 or 2 ml over a further 35 min. At the end of each experiment a 2 ml 0.9% saline bolus was given. Analysis of gentamicin collected at 5-min intervals was by an HPLC method. Key findings The experiment demonstrated that under the infusion conditions neonates weighing 2.5 kg would receive only 80% of the drug at 60 min, increasing to 90–95% by 75 min. In extremely low birth weight neonates (0.5 kg), even lower percentage of gentamicin recovery occurred. At 60 min only 60% of the intended gentamicin dose had been delivered and this increased to only 70% by 75 min. Conclusions The delivery of gentamicin administered by intravenous infusion is substantially extended in extremely low birth weight neonates. This appeared to be primarily due to the small volumes and low infusion rates used in these patients.

Purpose To examine the pharmacokinetics of amikacin and its pharmacokinetic pharmacodynamic (PKPD) relationship in neonates. To develop an alternative dosing strategy for amikacin in neonates. Methods A population PKPD analysis was performed using data collected from 80 neonates with gestational ages from 24 to 41 weeks. The final pharmacokinetic model analysed 358 amikacin concentrations. All neonates were >72 hours postnatal age. Simulations were performed to develop a new dosing strategy. Results The final covariate model was clearance=0.23× (current weight/2) 0.691 ×(postmenstrual age/40) 3.23 and volume of distribution=0.957×(current weight/2) 0.89 . Following the logistic regression analysis of treatment failure, new amikacin target concentrations were estimated and used in development of an alternative dosing strategy. Conclusion Simulation of a new dosing regimen yielded the following recommendations: 15 mg/kg at 36-h intervals, 14 mg/kg at 24-h intervals and 15 mg/kg at 24-h intervals for neonates ≤28 weeks, 29–36 weeks and ≥37 weeks postmenstrual age respectively.

We compared the test characteristics of interleukin (IL)-1 beta, IL-6, IL-8, IL-10, IL-12(p-70), tumor necrosis factor-alpha (TNF-alpha), procalcitonin (PCT), C-reactive protein (CRP), and full blood count (FBC) in the diagnosis of neonatal sepsis. This prospective cohort study in the Neonatal Intensive Care Unit of Dunedin hospital of patients between July 1, 2002 and February 28, 2007 included 117 neonates commenced on antibiotics for 164 episodes of suspected sepsis. Blood cultures, FBC, CRP, IL-1 beta, IL-6, IL-8, IL-10, IL-12(p-70), TNF-alpha, and PCT were obtained at the time sepsis was first suspected and for the following 3 days. Receiver operator characteristics (ROC) plots and test characteristics were determined using culture-positive sepsis as the gold standard. At the time sepsis was first suspected, the most promising individual test was IL-12(p70) with an area under the curve (95% confidence interval [CI]) for the ROC of 0.74 (0.63 to 0.86), which (with a cutoff at 75 pg/mL) had a sensitivity (95% CI) of 28% (20 to 36%) and a specificity of 98% (96 to 100%). IL-10 had a sensitivity of 17% (10 to 23%) and a specificity of 99% (97 to 100%). IL-10 and IL-12(p70) are promising diagnostic tests that can be used to confirm sepsis in neonates.

The aim of this study was develop an optimal dosing regimen for netilmicin in neonates.This was a population pharmacokinetic study in 97 neonates aged from 2 to 28 days after the due date who were being treated with netilmicin for suspected sepsis. The model was used to simulate dosing regimens.The principle factors influencing netilmicin clearance (CL) were postmenstrual age (PMA) and current body weight (CWT), and the principal determinant of volume of distribution (V) was CWT. The final covariate model was CL = 0.192 x (CWT/2)(1.35) x (PMA/40)(1.03), V = 1.5 x (CWT/2)(0.3). The optimal dosing was 5 mg/kg ever 36 h, 5 mg/kg every 24 h, 6 mg/kg every 24 h and 7 mg/kg every 24 h for neonatesor =27, 28-30, 31-33 andor =34 weeks PMA, respectively.Individualisation of netilmicin dosing in neonates requires adjustment of dose by body weight, and dosing interval by both PMA and CWT.

During pregnancy, important physiologic changes occur that affect pharmacokinetics and ultimately drug management. These include changes to renal and liver function, changes in serum protein levels, and the addition of a pharmacokinetic compartment (the infant and placenta) that is not present in the broader population. In addition, postpartum return to baseline physiology can further complicate drug management. This chapter examines therapeutic drug monitoring issues associated with pregnancy, including specific examples such as management of antidepressants.

This study sought to assess the pharmacokinetic (PK) changes of caffeine and its CYP1A2 metabolites across the 3 trimesters of pregnancy. A prospective, multicenter PK study was conducted among 59 pregnant women (93.2% white) who were studied once during a trimester. One beverage with 30-95 mg caffeine was consumed, and a blood/urine sample was collected within 1 hour postingestion. Concentrations of caffeine and its primary metabolites were quantified from serum and urine by LC-MS/MS. There was a significant increase in dose-normalized caffeine serum and urine concentrations between the first and third trimesters (P

The treatment of newborns with safe and effective medicines is of critical importance for their outcome and subsequent quality of life. Despite this, it is still a common practice to prescribe medicines to neonates outside the label, extrapolating from dosing regimens and indications validated in older populations and based on non-neonatal pathophysiology. In a recent meta-analysis (2015) evaluating 829 (1994–2012) studies on prescribing practices in pediatric hospital care, off-label and unlicensed medicines prescriptions ranged from 12 to 71 % and 0.2 to 48 %. These authors hereby reconfirmed that (pre)term neonates were still most commonly exposed to off-label and unlicensed medicines [12]. The federal US legislation and similar European initiatives have resulted in a relevant increase in pharmacological studies in children, with a subsequent significant increase in label changes. Unfortunately, too few included drug label changes specific to neonates. To further illustrate this, there were 406 pediatric label changes (Food and Drug Administration, 1997–2010), but only 23 drugs resulted in 11 labeled indications (e.g., linezolid, rocuronium, remifentanil, sevoflurane, stavudine, nevirapine) for neonates. The absence of label change was most commonly because of unproven efficacy, despite the fact that these compounds (e.g., paracetamol, caspofungin, valganciclovir) are likely relevant for neonates [14]. This may largely reflect the difficulties to proof efficacy due to heterogeneity in patients, variability in outcome variables, and uncertainty on biomarkers, in addition to demonstrating safety (risk of adverse drug events) in neonates. Despite the significant improvements in the knowledge on pharmacotherapy in older children, neonates still remain therapeutic orphans [2, 14]. In this issue of the journal, Campino et al. report on the rate of errors (calculation or accuracy) in intravenous medicine preparations when performed either bedside in 10 Spanish neonatal intensive care units (NICUs) or in hospital pharmacy (HP) services. The study group hereby evaluated the impact of a structured intervention (protocol standardization, education) on the number of errors and documented significant improvements in both calculation errors (1.35 to 0 %) and accuracy (54.7 and 38.3 % to 38.3 and 14.6 % in NICU and HP, respectively) [6]. This intervention paper follows on a previous paper which described a pre-intervention phase [5] and illustrates the potential impact of preventive strategies on the extent of drug errors. Development of a roadmap to improve neonatal pharmaceutical care should aim to improve the knowledge on clinical pharmacology, clinical pharmacy, and approaches to improve the knowledge and use of neonatal pharmacovigilance initiatives [1]. Another keystone component of such a roadmap should focus on neonatal drug development, i.e., drug development driven by neonatal pathophysiology (Fig. 1). Communicated by Patrick Van Reempts

In the United States, the incidence of osteoarticular infections among hospitalized children increased 15% from 2.07 to 2.38 cases per 1000 admissions from 1997 through 2012. The incidence of methicillin-resistant Staphylococcus aureus-coded infections increased from 0.02 to 0.36 cases per 1000 admissions. Methicillin-resistant S. aureus-coded cases had a larger number of therapeutic procedures, longer hospital stays and higher hospital charges.

Background The incidence of nephrotoxicity among vancomycin-treated neonates has been reported to range from 2% to 20%. These widely varying estimates have led to confusion and controversy regarding the safety of vancomycin among neonates. Objective Evaluate the incidence of nephrotoxicity among neonates receiving vancomycin concomitantly with gentamicin. Design Retrospective observational cohort study using propensity score matching to provide covariate balance between neonates who did or did not receive vancomycin based on factors known to be related to the development of renal dysfunction. Setting Hospitals (n=22) throughout the Intermountain West, including a quaternary care children9s hospital. Patients Neonates ≤44 postmenstrual weeks (median gestational age: 31 (IQR 28–36) weeks) receiving intravenous gentamicin with or without exposure to vancomycin from January 2006 to December 2012. Main outcome measures Nephrotoxicity based on the modified Acute Kidney Injury Network criteria for acute kidney injury (AKI) or serum creatinine concentration ≥1.5 mg/dL persisting for ≥48 h. Results The final cohort was comprised of 1066 neonates (533 receiving vancomycin and gentamicin vs 533 receiving gentamicin). In a propensity score-matched cohort that was well balanced across 16 covariates, AKI was not associated with vancomycin use (16 neonates receiving vancomycin vs 7 controls experienced AKI; OR 1.5; 95% CI 0.6 to 4.0). However, the presence of a patent ductus arteriosus, concomitant non-steroidal anti-inflammatory drug use, ≥1 positive blood cultures, low birth weight and higher severity of illness and risk of mortality scores were associated with an increased risk of nephrotoxicity. Conclusions These results corroborate several earlier reports and much anecdotal evidence describing the infrequent occurrence of nephrotoxicity in neonates receiving concomitant vancomycin and gentamicin.

We have devised a simple assay to detect adequate biotin intake, which uses an alternative configuration from most existing assays.The assay depends on the competition of streptavidin peroxidase for immobilized biotin or soluble biotin in standards or samples. Immobilized streptavidin peroxidase is detected using tetramethylbenzidine, and the plates are read at 450 nm. The assay was normalised by determining the biotin/creatinine ratio in the urine of healthy adults. Urinary biotin excretion was measured in unsupplemented pregnant women. The half-life of biotin excretion after a single oral supplement was determined for healthy volunteers.Urinary biotin excretion in unsupplemented pregnant women was 2.9+/-1.9 micromol/mol creatinine (mean+/-S.D.) and was significantly lower (p0.001) than those of healthy males and females, which were 9.0+/-5.4 and 7.0+/-2.1 micromol/mol creatinine (mean+/-S.D.), respectively. The half-life of a single oral biotin supplement was 30-40 h, with excretion returning to basal levels at 70 h.We have devised a novel binding assay for the direct determination of total biotin excretion in urine, which is suitable for routine clinical laboratory. The assay is inexpensive, simple, rapid, and could be fully automated.

Several species of mice build burrows, however, little is known about the motivation underlying this behaviour. This study had two aims: (1) to investigate whether burrowing constitutes a behavioural need, that is, whether mice were motivated to perform the behaviour of burrowing per se, or whether it is the functional consequences of burrowing that motivate the behaviour; (2) to determine the strength of motivation that laboratory mice have for burrowing. In Experiment 1, eight BALB/c mice were placed individually into a start cage connected to two burrowing compartments containing peat. During Phase 1, the mice had access to only one compartment, and during Phase 2, access to only the second. At the beginning of Phase 3, the burrows in one of the compartments were destroyed and the mice given access to both. The duration of burrowing remained unchanged throughout all three phases, and the number of burrowing bouts significantly increased. During Phase 3, there was no significant difference between burrowing in the compartments containing the intact or the destroyed burrows. These data confirmed that laboratory mice readily build burrows when given the opportunity, and indicate this behaviour constitutes a ‘behavioural need’. In Experiment 2, the strength of motivation for burrowing was examined in five CB57 mice using an operant technique in which a single mouse within a group could work to gain access to burrowing substrate. Despite increasing cost of gaining access, the mice continued to work to visit the burrowing substrate. The slope and area under the demand function indicated that the motivation to build burrows was high. These findings indicate that if studies require laboratory mice to express a full behavioural repertoire, or to avoid compromises of welfare, mice should be provided with the opportunity to perform burrowing wherever practicable.

Mirrors have been suggested as a potential environmental enrichment for animals that are individually housed. The present study examined the influence of a mirror on the behaviour of individually housed laboratory mice. Sixteen mice were placed into apparatus comprised of two preference cages connected by a tunnel. A mirror was placed in one of the preference cages (mirror) but not in the other (non-mirror) and the position swapped daily for 4 days. Thirteen of the 16 mice spent less time in the mirror cage than the non-mirror cage (Sign test; P=0.021) indicating an aversion to the mirror, however, the difference in occupation of the cages was not great. Overall, the mice occupied the mirror cage 47.6±4.7% of the time and the non-mirror cage 52.4±4.7%. There was no significant effect of the mirror on the number of mice building a nest in the mirror (N=10) or the non-mirror cage (N=6). The presence of the mirror significantly reduced feeding from the immediately adjacent feeder. The number of bouts, total time, and the mean feeding bout duration were all decreased by approximately 50–60% (ANOVA; P

Despite therapeutic hypothermia, neonates with encephalopathy (NE) have high rates of death or disability. Darbepoetin alfa (Darbe) has comparable biological activity to erythropoietin, but has extended circulating half-life (t(1/2)). Our aim was to determine Darbe safety and pharmacokinetics as adjunctive therapy to hypothermia.Thirty infants (n = 10/arm) ≥36 wk gestation undergoing therapeutic hypothermia for NE were randomized to receive placebo, Darbe low dose (2 μg/kg), or high dose (10 μg/kg) given intravenously within 12 h of birth (first dose/hypothermia condition) and at 7 d (second dose/normothermia condition). Adverse events were documented for 1 mo. Serum samples were obtained to characterize Darbe pharmacokinetics.Adverse events (hypotension, altered liver and renal function, seizures, and death) were similar to placebo and historical controls. Following the first Darbe dose at 2 and 10 μg/kg, t(1/2) was 24 and 32 h, and the area under the curve (AUC(inf)) was 26,555 and 180,886 h*mU/ml*, respectively. In addition, clearance was not significantly different between the doses (0.05 and 0.04 l/h). At 7 d, t(1/2) was 26 and 35 h, and AUC(inf) was 10,790 and 56,233 h*mU/ml*, respectively (*P0.01).Darbe combined with hypothermia has similar safety profile to placebo with pharmacokinetics sufficient for weekly administration.

Acute myeloid leukemia (AML) is a clonal hematological malignancy characterized by accumulation of poorly differentiated and immature blast cells in bone marrow and blood circulation. The initiation of intensive chemotherapy is necessary to control further progression of the disease. Therapeutic success is less common in older patients (65 years) than it is in younger patients with AML. Cytarabine in combination with an anthracycline has been the mainstays of AML therapy for many years and continues to serve as the foundation for the current standard therapeutic regimen.This review discusses the pharmacokinetic (PK), metabolic and toxicological issues associated with antileukemic agents used to treat elderly patients (60 years) with AML.Profound and predictable changes often occur with age and can have effects on drug metabolism, PK and toxicity with consequences bearing on overall efficacy. Few studies focus specifically on elderly patients with AML, but modifications to intensive induction therapy may be beneficial as the current number and rate of individuals achieving complete remission of the disease remains low. Therapeutic options, for the treatment of AML, have remained static for many years, but it has become clear that among elderly patients with AML, improved antileukemic therapy is greatly needed.

Among infants and immunocompromised children cytomegalovirus (CMV) is associated with significant morbidity and mortality.This review describes the clinical pharmacokinetics and pharmacodynamics of ganciclovir and valganciclovir for the treatment and prevention of CMV infection in children.A 24-h ganciclovir area under the concentration versus time curve (AUC₀₋₂₄) of 40 - 60 μg h/ml decreased the risk of CMV infection for adults undergoing CMV prophylaxis. For adults undergoing treatment for active CMV disease, a target AUC₀₋₁₂ of 40 - 60 μg h/ml has been suggested. The applicability of these targets to children remains uncertain; however, with the most sophisticated dosing regimens developed to date only 21% of patients are predicted to reach these targets. Moving forward, identification of optimal pediatric ganciclovir and valganciclovir dosing regimens may involve the use of an externally validated pediatric population pharmacokinetic model for empirical dosing, an optimal sampling strategy for collecting a minimal number of blood samples for each patient and Bayesian updating of the dosing regimen based on an individual patient's pharmacokinetic profile.

Chronic pulmonary infections are common among patients with cystic fibrosis. By 10 years of age, Pseudomonas aeruginosa is the predominant pathogen. Inhaled levofloxacin solution (MP-376) is a promising new therapy that exhibits rapid antibacterial activity and excellent biofilm penetration against P. aeruginosa. In the largest trial to date, 151 patients were randomized to receive MP-376 or placebo. At the end of the 28-day treatment period, patients who received MP-376 had decreased P. aeruginosa density in sputum, improved lung function parameters and improved respiratory symptoms. MP-376 also appeared to be safe and well tolerated. The results of two recently completed Phase III trials have not yet been released; however, these data will be critical in determining whether MP-376 is a safe and effective maintenance therapy for chronic pulmonary P. aeruginosa infections among patients with cystic fibrosis.

Objective: Chronic neurological deficits are a significant complication of preterm birth. Magnesium supplementation has been suggested to have neuroprotective function in the developing brain. Our objective was to determine whether higher neonatal serum magnesium levels were associated with better long-term neurodevelopmental outcomes in very-low birth weight infants. Study Design: A retrospective cohort of 75 preterm infants (

It is not trivial to conduct clinical trials with pediatric participants. Ethical, logistical, and financial considerations add to the complexity of pediatric studies. Optimal design theory allows investigators the opportunity to apply mathematical optimization algorithms to define how to structure their data collection to answer focused research questions. These techniques can be used to determine an optimal sample size, optimal sample times, and the number of samples required for pharmacokinetic and pharmacodynamic studies. The aim of this review is to demonstrate how to determine optimal sample size, optimal sample times, and the number of samples required from each patient by presenting specific examples using optimal design tools. Additionally, this review aims to discuss the relative usefulness of sparse vs rich data. This review is intended to educate the clinician, as well as the basic research scientist, whom plan on conducting a pharmacokinetic/pharmacodynamic clinical trial in pediatric patients.

This review aims to critically evaluate the pharmacokinetic literature describing the use of vancomycin in the treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections. Guidelines recommend that trough concentrations be used to guide vancomycin dosing for the treatment of MRSA infections; however, numerous in vitro, animal model and clinical studies have demonstrated that the therapeutic effectiveness of vancomycin is best described by the area under the concentration versus time curve (AUC) divided by the minimum inhibitory concentration (MIC) of the infecting organism (AUC/MIC). Among patients with lower respiratory tract infections, an AUC/MIC ≥400 was associated with a superior clinical and bacteriological response. Similarly, patients with MRSA bacteremia who achieved an Etest AUC/MIC ≥320 within 48 h were 50% less likely to experience treatment failure. For other patient populations and different clinical syndromes (e.g., children, the elderly, patients with osteomyelitis, etc.), pharmacokinetic/pharmacodynamic studies and prospective clinical trials are needed to establish appropriate therapeutic targets.

Zolpidem is a short-acting non-benzodiazepine hypnotic that is used to improve sleep architecture in patients with burn injuries. This study evaluated the relationship between zolpidem administration and sleep parameters in a cohort of children with severe burn injuries. Standard age-based zolpidem dosing practices were employed. Polysomnography data were recorded at 30-second intervals throughout the night. Serum concentrations of zolpidem were measured at 0, 1, 2, 4, 5, 6, and 8 hours after administration of the first dose. The relationship between zolpidem concentrations and sleep parameters was evaluated using Markov mixed-effects pharmacodynamic models. Ten children received two doses of zolpidem at 22:00 and 02:00 hours. The median total amount of sleep was 361.0 (interquartile range [IQR]: 299.0–418.5) minutes; approximately 65% of the normal reference value for an 8-hour period. Slow-wave and rapid eye movement (REM) sleep were also dramatically reduced (18–37% of normal). With two doses of zolpidem, stage 2 sleep was 99% of normal levels. Higher peak zolpidem concentrations were associated with increased stage 2 sleep (r2 = .54; P = .04). Despite this, a median of 120.0 (IQR: 99.5–143.5) transitions between nocturnal sleep stages were recorded, with a median of 55.5 (IQR: 36–75) night-time awakenings per patient. In pediatric burn patients, higher zolpidem serum concentrations were associated with restoration of stage 2 sleep to normal levels. Nonetheless, slow-wave and REM sleep were profoundly depressed with frequent transitions between sleep stages, suggesting that alternative hypnotic agents may be required to restore normal sleep architecture in severely burned children.

This study aimed to develop optimal amikacin dosing regimens for the empirical treatment of Gram-negative bacterial sepsis in pediatric patients with burn injuries. A pharmacodynamic (PD) target in which the peak concentration (Cmax) is ≥8 times the minimum inhibitory concentration (MIC) (Cmax/MIC ≥ 8) is reflective of optimal bactericidal activity and has been used to predict clinical outcomes. Population pharmacokinetic modeling was performed in NONMEM 7.2 for pediatric patients with and without burn injuries. Amikacin pharmacokinetic parameters were compared between the two groups and multiple dosing regimens were simulated using MATLAB to achieve the PD target in ≥90% of patients with burn injuries. The pharmacokinetic analysis included 282 amikacin concentrations from 70 pediatric patients with burn injuries and 99 concentrations from 32 pediatric patients without burns. A one-compartment model with first-order elimination described amikacin pharmacokinetics well for both groups. Clearance (CL) was significantly higher in patients with burn injuries than in patients without (7.22 vs 5.36 L/h, P < .001). The volume of distribution (V) was also significantly increased in patients with burn injuries (22.7 vs 18.7 L, P < .01). Weight significantly influenced amikacin CL (P < .001) and V (P < .001) for both groups. Model-based simulations showed that a higher amikacin dose (≥25 mg/kg) achieved a Cmax/MIC ≥8 in ≥90% of patients with assumed infections of organisms with an MIC = 8 mg/L. Amikacin pharmacokinetics are altered in patients with burn injuries, including a significant increase in CL and V. In simulations, increased doses (≥25 mg/kg) led to improved PD target attainment rates. Further clinical evaluation of this proposed dosing regimen is warranted to assess clinical and microbiological outcomes in pediatric patients with burn wound sepsis.

BackgroundIntravenous racemic ketamine is commonly administered for procedural sedation, although few pharmacokinetic studies have been conducted among children. Moreover, an optimal sampling schedule has not been derived to enable the conduct of pharmacokinetic studies that minimally inconvenience study participants.MethodsConcentration-time data were obtained from 57 children who received 1-1.5 mg.kg(-1) of racemic ketamine as an intravenous bolus. A population pharmacokinetic analysis was conducted using nonlinear mixed effects models, and the results were used as inputs to develop a D-optimal sampling schedule.ResultsThe pharmacokinetics of ketamine were described using a two-compartment model. The volume of distribution in the central and peripheral compartments were 20.5 l.70 kg(-1) and 220 l.70 kg(-1), respectively. The intercompartmental clearance and total body clearance were 87.3 and 87.9 l.h(-1).70 kg(-1), respectively. Population parameter variability ranged from 34% to 98%. Initially, blood samples were drawn on 3-6 occasions spanning a range of 14-152 min after dosing. Using these data, we determined that four optimal sampling windows occur at 1-5, 5.5-7.5, 10-20, and 90-180 min after dosing. Monte Carlo simulations indicated that these sampling windows produced precise and unbiased ketamine pharmacokinetic parameter estimates.ConclusionAn optimal sampling schedule was developed that allowed assessment of the pharmacokinetic parameters of ketamine among children requiring short-term procedural sedation.

Antimicrobials and antivirals are widely used in young infants and neonates. These patients have historically been largely excluded from clinical trials and, as a consequence, the pharmacokinetics and pharmacodynamics of commonly used antibacterials, antifungals, and antivirals are incompletely understood in this population. This review summarizes the current literature specific to neonates and infants regarding pharmacokinetic parameters and changes in neonatal development that affect antimicrobial and antiviral pharmacodynamics. Specific drug classes addressed include aminoglycosides, aminopenicillins, cephalosporins, glycopeptides, azole antifungals, echinocandins, polyenes, and guanosine analogs. Within each drug class, the pharmacodynamics, pharmacokinetics, and clinical implications and future directions for prototypical agents are discussed. β-Lactam antibacterial activity is maximized when the plasma concentration exceeds the minimum inhibitory concentration for a prolonged period, suggesting that more frequent dosing may optimize β-lactam therapy. Aminoglycosides are typically administered at longer intervals with larger doses in order to maximize exposure (i.e., area under the plasma concentration–time curve) with gestational age and weight strongly influencing the pharmacokinetic profile. Nonetheless, safety concerns necessitate therapeutic drug monitoring across the entire neonatal and young infant spectrum. Vancomycin, representing the glycopeptide class of antibacterials, has a long history of clinical utility, yet there is still uncertainty about the optimal pharmacodynamic index in neonates and young infants. The high degree of pharmacokinetic variability in this population makes therapeutic drug monitoring essential to ensure adequate therapeutic exposure. Among neonates treated with the triazole agent fluconazole, it has been speculated that loading doses may improve pharmacodynamic target attainment rates. The use of voriconazole necessitates therapeutic drug monitoring and dose adjustments for patients with hepatic dysfunction. Neonates treated with lipid-based formulations of the polyene amphotericin B may be at an increased risk of death, such that alternative antifungal agents should be considered for neonates with invasive fungal infections. Alternative antifungal agents such as micafungin and caspofungin also exhibit unique pharmacokinetic considerations in this population. Neonates rapidly eliminate micafungin and require nearly three times the normal adult dose to achieve comparable levels of systemic exposure. Conversely, peak caspofungin concentrations have been reported to be similar among neonates and adults. However, both of these drugs feature favorable safety profiles. Recent studies with acyclovir have suggested that current dosing regimens may not result in therapeutic central nervous system concentrations and more frequent dosing may be required for neonates at later postmenstrual ages. Though ganciclovir and valganciclovir demonstrate excellent activity against cytomegalovirus, they are associated with significant neutropenia. In summary, many pharmacokinetic and pharmacodynamic studies have been conducted in this vulnerable population; however, there are also substantial gaps in our knowledge that require further investigation. These studies will be invaluable in determining optimal neonatal dosing regimens that have the potential to improve clinical outcomes and decrease adverse effects associated with antimicrobial and antiviral treatments.

Invasive fungal infections are a significant cause of morbidity and mortality in children. Successful management of these systemic infections requires identification of the causative pathogen, appropriate antifungal selection, and optimisation of its pharmacokinetic and pharmacodynamic properties to maximise its antifungal activity and minimise toxicity and the emergence of resistance. This review highlights salient scientific advancements in paediatric antifungal pharmacotherapies and focuses on pharmacokinetic and pharmacodynamic studies that underpin current clinical decision making. Four classes of drugs are widely used in the treatment of invasive fungal infections in children, including the polyenes, triazoles, pyrimidine analogues and echinocandins. Several lipidic formulations of the polyene amphotericin B have substantially reduced the toxicity associated with the traditional amphotericin B formulation. Monotherapy with the pyrimidine analogue flucytosine rapidly promotes the emergence of resistance and cannot be recommended. However, when used in combination with other antifungal agents, therapeutic drug monitoring of flucytosine has been shown to reduce high peak flucytosine concentrations, which are strongly associated with toxicity. The triazoles feature large inter-individual pharmacokinetic variability, although this pattern is less pronounced with fluconazole. In clinical trials, posaconazole was associated with fewer adverse effects than other members of the triazole family, though both posaconazole and itraconazole display erratic absorption that is influenced by gastric pH and the gastric emptying rate. Limited data suggest that the clinical response to therapy may be improved with higher plasma posaconazole and itraconazole concentrations. For voriconazole, pharmacokinetic studies among children have revealed that children require twice the recommended adult dose to achieve comparable blood concentrations. Voriconazole clearance is also affected by the cytochrome P450 (CYP) 2C19 genotype and hepatic impairment. Therapeutic drug monitoring is recommended as voriconazole pharmacokinetics are highly variable and small dose increases can result in marked changes in plasma concentrations. For the echinocandins, the primary source of pharmacokinetic variability stems from an age-dependent decrease in clearance with increasing age. Consequently, young children require larger doses per kilogram of body weight than older children and adults. Routine therapeutic drug monitoring for the echinocandins is not recommended. The effectiveness of many systemic antifungal agents has been correlated with pharmacodynamic targets in in vitro and in murine models of invasive candidiasis and aspergillosis. Further study is needed to translate these findings into optimal dosing regimens for children and to understand how these agents interact when multiple antifungal agents are used in combination.

The objective of this study was to assess the frequency of blood culture (BC) collection among neonates who received vancomycin. Demographic, clinical, microbiologic, and pharmacy data were collected for 1275 neonates (postnatal age 0–27 days) who received vancomycin at an Intermountain Healthcare facility between 1/2006 and 9/2011. Neonates treated with vancomycin had a BC collected 94 % (n = 1198) of the time, of which 37 % (n = 448) grew one or more bacterial organisms (BC positive). Of these, 1 % (n = 5) grew methicillin-resistant Staphylococcus aureus (MRSA), 71 % (n = 320) grew coagulase-negative Staphylococci (CoNS), 9 % (n = 40) grew methicillin-sensitive Staphylococcus aureus (MSSA), and 22 % (n = 97) grew other bacterial species (total exceeds 100 % due to co-detection). In patients with negative BC or no BC, vancomycin therapy was extended beyond 72 h 52 % of the time. The median duration of vancomycin therapy for patients with a negative BC was 4 (IQR: 2–10) days. BCs were frequently obtained among neonates who received vancomycin. Vancomycin therapy beyond the conventional ‘empiric’ treatment window of 48–72 h was common without isolation of resistant gram-positive bacteria.

BACKGROUND This study sought to determine the frequency of possible cardiopulmonary drug-drug interactions among pregnant women who received intrapartum magnesium sulfate (MgSO4). METHODS Pregnant women admitted to an Intermountain Healthcare facility between January 2009 and October 2011 were studied, if they received 1 or more doses of MgSO4. Concomitant medications were electronically queried from an electronic health records system. Adverse events were identified using administrative discharge codes. The frequency of cardiopulmonary drug-drug interactions was compared among women who did, and did not, receive aminoglycoside antibiotics, antacids/laxatives, calcium channel blockers, corticosteroids, diuretics, neuromuscular blocking agents, and vitamin D analogs, all of which were contraindicated for patients receiving MgSO4. RESULTS Overall, 683 women received intrapartum MgSO4 during the study period. A total of 219 MgSO4 potentially interacting drugs were identified among 155 (23%) unique patients. The most commonly identified potentially interacting agents included calcium channel blockers (26%), diuretics (25%), and antacids/laxatives (19%). Longer hospital stays were significantly associated with increasing numbers of MgSO4 interacting drugs (P < 0.001). Three of 53 (6%) women who received furosemide experienced a cardiac arrest, compared with 0 of 618 (0%) women who did not receive furosemide (Fisher exact test, P < 0.001). CONCLUSIONS Intrapartum administration of drugs that interact with MgSO4 is common and associated with prolonged hospital stays and potentially cardiopulmonary drug-drug interactions. Caution is warranted when prescribing MgSO4 in combination with known interacting medications.

Multiple blood samples are generally required for measurement of pharmacokinetic (PK) parameters. D-optimal design is a popular and frequently used approach for determination of sampling time points in order to minimize the number of samples, while optimizing the estimation of PK parameters. Optimal design utilizing ADAPT (v5, BSR, University of Southern California, Los Angeles) developed a sparse sampling strategy to determine measurement of propofol in pregnant sheep. Propofal was administered as supplemental anesthetic agent to inhalation anesthesia to mimic anesthesia for open fetal surgery. In our preliminary study, propofol 3 mg/kg was given as a bolus to the ewe, followed by propofol infusion at rate 450 mcg/kg/min for 60 minutes, then decreased to 75 mcg/kg/min for 90 more minutes and then ceased. A three compartment model described the PK parameters with the fetus assumed as the third compartment. Initially, sampling times were chosen from thirteen time points as previously stated in the literature. Using priori propofol PK estimates, the final 9 sample time points were proposed in an optimal design with a change in infusion rate occurring between 65 and 75 minutes and sampling proposed at 5, 15, 25, 65, 75, 100, 110, 150, and 180 minutes. D-optimal design optimized the number and timing of samplings, which led to a reduction of cost and man power in the study protocol while preserving the ability to estimate propofol PK parameters in the maternal and fetal sheep model. Initial evaluation of samples collected from three sheep using the optimal design strategy confirmed the performance of the design in obtaining effective PK parameter estimates.

Ultraviolet (UV) sensitivity in birds has been shown to be intrinsically involved in the selection of mates; UV may, therefore, also play a role in the establishment and maintenance of social hierarchies in intensively housed turkeys. Cereal seeds and straw are known to reflect UV, and turkeys may use these cues for foraging and exploratory behaviors. A series of trials was conducted to see if supplementation of the photoperiod (12 h at various white light intensities) with UV radiation (0.06 to 0.16 W/m2 at floor level) and regular supplies of straw to the litter allow a better recognition of individuals within a flock, enrich the environment by the provision of new pecking material and of radiation across the whole range of avian sensitivity, and, as a consequence, reduce the incidence of injurious pecking in male turkeys that have not been beak-trimmed, detoed, or desnooded. Body weight gain, feed intake, feed conversion efficiency, and leg integrity were generally not significantly affected by UV supplementation and environmental enrichment. In contrast, the provision of UV radiation, simultaneous with a 12-h photoperiod of white light at intensities of70 lx to 5 wk and of 10 lx to 20 wk, and the regular addition of straw to the litter, significantly reduced the incidence of culling because of injurious pecking. However, complex interactions among UV supplementation, white light intensity, and material environmental enrichment precluded a simple recommendation to solve the problem of injurious pecking.