Association of delayed adequate antimicrobial treatment and organ dysfunction in pediatric bloodstream infections.

BACKGROUND: Bloodstream infections (BSIs) are associated with significant mortality and morbidity, including multiple organ dysfunction. We explored if delayed adequate antimicrobial treatment for children with BSIs is associated with change in organ dysfunction as measured by PELOD-2 scores. METHODS: We conducted a multicenter, retrospective cohort study of critically ill children <18 years old with BSIs. The primary outcome was change in PELOD-2 score between days 1 (index blood culture) and 5. The exposure variable was delayed administration of adequate antimicrobial therapy by ≥3 h from blood culture collection. We compared PELOD-2 score changes between those who received early and delayed treatment. RESULTS: Among 202 children, the median (interquartile range) time to adequate antimicrobial therapy was 7 (0.8-20.1) hours; 124 (61%) received delayed antimicrobial therapy. Patients who received early and delayed treatment had similar baseline characteristics. There was no significant difference in PELOD-2 score changes from days 1 and 5 between groups (PELOD-2 score difference -0.07, 95% CI -0.92 to 0.79, p = 0.88). CONCLUSIONS: We did not find an association between delayed adequate antimicrobial therapy and PELOD-2 score changes between days 1 and 5 from detection of BSI. PELOD-2 score was not sensitive for clinical effects of delayed antimicrobial treatment. IMPACT: In critically ill children with bloodstream infections, there was no significant change in organ dysfunction as measured by PELOD-2 scores between patients who received adequate antimicrobial therapy within 3 h of their initial positive blood culture and those who started after 3 h. Higher PELOD-2 scores on day 1 were associated with larger differences in PELOD-2 scores between days 1 and 5 from index positive blood cultures. Further study is required to determine if PELOD-2 or alternative measures of organ dysfunction could be used as primary outcome measures in trials of antimicrobial interventions in pediatric critical care research.

Association between vancomycin therapeutic drug monitoring and clinical outcomes in treating neonatal sepsis.

BACKGROUND: Neonatal sepsis is commonly treated with vancomycin in the neonatal intensive care unit. Therapeutic drug monitoring of vancomycin is routinely used to personalise dosing to optimise effectiveness and avoid toxicity. OBJECTIVES: This study aimed to define a target range by evaluating associations between vancomycin trough concentrations or area under the concentration time curve over 24 hours (AUC24h) and clinical outcomes in neonates. METHODS: Neonates, who were admitted to the neonatal intensive care unit and received intravenous vancomycin, were included in this retrospective cohort study. For evaluating effectiveness, patients who received vancomycin for < 5 days were excluded. The AUC24h was estimated based on a study-derived population pharmacokinetic model. Primary outcomes were persistent/recurrent infections and mortality within 30 days. Secondary outcomes, including acute kidney injury (AKI), were also assessed. Logistic regression and classification and regression tree analyses were performed. RESULTS: A total of 448 patients (123 patients for effectiveness analysis) were included. A vancomycin trough > 10 mg/L was associated with 70% lower odds of persistent/recurrent infections (adjusted OR 0.30, 95% CI 0.09-0.86; P = 0.023). Patients who took more than a day to reach target range had 1.4 times higher odds of persistent/recurrent infections or death (P = 0.04). A vancomycin trough > 15 mg/L was associated with a three times higher risk of AKI (P = 0.003). An AUC24h of 420-650 mg*h/L was also associated with the lowest risk of composite outcomes (adjusted OR 0.29, 95% CI 0.08-0.86; P = 0.025). CONCLUSION: A vancomycin trough target range of 10-15 mg/L and achievement of this target within a day of treatment initiation were associated with the most optimal clinical outcomes in treating neonatal sepsis.

Using population pharmacokinetics to optimize initial vancomycin dosing guidelines for neonates to treat sepsis caused by coagulase-negative staphylococcus.

INTRODUCTION: Vancomycin dosing tailored for newborns is challenging due to the significant influence of maturation and organ function on pharmacokinetics. Population pharmacokinetic (popPK) models can be used to improve target attainment in neonates. OBJECTIVES: The primary objective was to derive and evaluate a popPK model of intravenous vancomycin for neonates. Second, the predictive performance of this popPK model was compared with published popPK models. METHODS: This is a retrospective cohort study of neonates admitted to the neonatal intensive care unit receiving intravenous vancomycin. A popPK model was derived with 70% of the dataset using a nonlinear mixed effects modeling method. The predictive performance of the current popPK model was validated and compared with 22 published popPK models using the remaining 30% of the dataset. Monte Carlo simulations (MCS) were performed to derive optimal dosing regimens to treat neonatal sepsis caused by coagulase-negative staphylococci (CoNS). RESULTS: Among 655 vancomycin courses from 448 neonates, 78% of vancomycin trough concentrations were outside target range (10-15 mg/L) for central nervous system infections and 43% were outside target range (5-12 mg/L) for other infections using the institution's vancomycin dosing. A one-compartment model best described the observed data with a mean clearance of 0.11 ± 0.03 L/kg/h and volume of distribution (V) of 1.02 ± 0.08 L/kg. Body weight (WT), postmenstrual age (PMA), and serum creatinine (SCr) were significant covariates associated with clearance (p < 0.001) and body WT was a significant covariate associated with V (p = 0.009). Our study's popPK model has similar or better accuracy and precision than other published models. MCS-derived vancomycin doses from the validated model achieved >90% target attainment for a steady state through target range of 10-15 mg/L in the majority of PMA and SCr categories (78%) to treat CoNS sepsis. CONCLUSION: A vancomycin dosing guideline derived from a validated popPK model in neonates with CoNS sepsis is recommended to improve target attainment.

Antibiotic treatment duration for bloodstream infections in critically ill children-A survey of pediatric infectious diseases and critical care clinicians for clinical equipoise.

OBJECTIVE: To describe antibiotic treatment durations that pediatric infectious diseases (ID) and critical care clinicians usually recommend for bloodstream infections in critically ill children. DESIGN: Anonymous, online practice survey using five common pediatric-based case scenarios of bloodstream infections. SETTING: Pediatric intensive care units in Canada, Australia and New Zealand. PARTICIPANTS: Pediatric intensivists, nurse practitioners, ID physicians and pharmacists. MAIN OUTCOME MEASURES: Recommended treatment durations for common infectious syndromes associated with bloodstream infections and willingness to enrol patients into a trial to study treatment duration. RESULTS: Among 136 survey respondents, most recommended at least 10 days antibiotics for bloodstream infections associated with: pneumonia (65%), skin/soft tissue (74%), urinary tract (64%) and intra-abdominal infections (drained: 90%; undrained: 99%). For central vascular catheter-associated infections without catheter removal, over 90% clinicians recommended at least 10 days antibiotics, except for infections caused by coagulase negative staphylococci (79%). Recommendations for at least 10 days antibiotics were less common with catheter removal. In multivariable linear regression analyses, lack of source control was significantly associated with longer treatment durations (+5.2 days [95% CI: 4.4-6.1 days] for intra-abdominal infections and +4.1 days [95% CI: 3.8-4.4 days] for central vascular catheter-associated infections). Most clinicians (73-95%, depending on the source of bloodstream infection) would be willing to enrol patients into a trial of shorter versus longer antibiotic treatment duration. CONCLUSIONS: The majority of clinicians currently recommend at least 10 days of antibiotics for most scenarios of bloodstream infections in critically ill children. There is practice heterogeneity in self-reported treatment duration recommendations among clinicians. Treatment durations were similar across different infectious syndromes. Under appropriate clinical conditions, most clinicians would be willing to enrol patients into a trial of shorter versus longer treatment for common syndromes associated with bloodstream infections.

Noninferiority Margin Size and Acceptance of Trial Results: Contingent Valuation Survey of Clinician Preferences for Noninferior Mortality.

OBJECTIVES: We used modified contingent valuation methodology to determine how noninferiority margin sizes influence clinicians' willingness to accept clinical trial results that compare mortality in critically ill children. METHODS: We surveyed pediatric infectious diseases and critical care clinicians in Canada, Australia, and New Zealand and randomized respondents to review 1 of 9 mock abstracts describing a noninferiority trial of bacteremic critically ill children assigned to 7 or 14 d of antibiotics. Each scenario showed higher mortality in the 7-d group but met noninferiority criterion. We explored how noninferiority margins and baseline mortality rates influenced respondent acceptance of results. RESULTS: There were 106 survey respondents: 65 (61%) critical care clinicians, 28 (26%) infectious diseases physicians, and 13 (12%) pharmacists. When noninferiority margins were 5% and 10%, 73% (24/33) and 79% (27/33) respondents would accept shorter treatment, compared with 44% (17/39) when the margin was 20% (P = 0.003). Logistic regression adjusted for baseline mortality showed 5% and 10% noninferiority margins were more likely to be associated with acceptance of shorter treatment compared with 20% margins (odds ratio [OR] 3.5, 95% confidence interval [CI]: 1.3-9.6, P = 0.013; OR 5.1, 95% CI: 1.8-14.6, P = 0.002). Baseline mortality was not a significant predictor of acceptance of shorter treatment. CONCLUSIONS: Clinicians are more likely to accept shorter treatment when noninferiority margins are ≤10%. However, nearly half of respondents who reviewed abstracts with 20% margins were still willing to accept shorter treatment. This is a novel application of contingent valuation methodology to elicit acceptance of research results among end users of the medical literature. HIGHLIGHTS: Clinicians are more likely to accept shorter treatment durations based on noninferior mortality results when the noninferiority margin is 5% or 10% than if the margin is 20%.However, nearly half of clinicians would still accept shorter-duration treatment as noninferior with margins of 20%.Baseline mortality does not independently predict acceptance of shorter-duration treatment.Contingent valuation is a novel approach to elicit the acceptance of research design parameters from the perspective of endusers of the medical literature.

Antimicrobial treatment duration for uncomplicated bloodstream infections in critically ill children: a multicentre observational study.

BACKGROUND: Bloodstream infections (BSIs) cause significant morbidity and mortality in critically ill children but treatment duration is understudied. We describe the durations of antimicrobial treatment that critically ill children receive and explore factors associated with treatment duration. METHODS: We conducted a retrospective observational cohort study in six pediatric intensive care units (PICUs) across Canada. Associations between treatment duration and patient-, infection- and pathogen-related characteristics were explored using multivariable regression analyses. RESULTS: Among 187 critically ill children with BSIs, the median duration of antimicrobial treatment was 15 (IQR 11-25) days. Median treatment durations were longer than two weeks for all subjects with known sources of infection: catheter-related 16 (IQR 11-24), respiratory 15 (IQR 11-26), intra-abdominal 20 (IQR 14-26), skin/soft tissue 17 (IQR 15-33), urinary 17 (IQR 15-35), central nervous system 33 (IQR 15-46) and other sources 29.5 (IQR 15-55) days. When sources of infection were unclear, the median duration was 13 (IQR 10-16) days. Treatment durations varied widely within and across PICUs. In multivariable linear regression, longer treatment durations were associated with severity of illness (+ 0.4 days longer [95% confidence interval (CI), 0.1 to 0.7, p = 0.007] per unit increase in PRISM-IV) and central nervous system infection (+ 17 days [95% CI, 6.7 to 27.4], p = 0.001). Age and pathogen type were not associated with treatment duration. CONCLUSIONS: Most critically ill children with BSIs received at least two weeks of antimicrobial treatment. Further study is needed to determine whether shorter duration therapy would be effective for selected critically ill children.

Medications Reconciled at Discharge Versus Admission Among Inpatients at a Children's Hospital.

BACKGROUND AND OBJECTIVES: Discharge prescription practices may contribute to medication overuse and polypharmacy. We aimed to estimate changes in the number and types of medications reported at inpatient discharge (versus admission) at a tertiary care pediatric hospital. METHODS: Electronic medication reconciliation data were extracted for inpatient admissions at The Hospital for Sick Children from January 1, 2016, to December 31, 2017 (n = 22 058). Relative changes in the number of medications and relative risks (RRs) of specific types and subclasses of medications at discharge (versus admission) were estimated overall and stratified by the following: sex, age group, diagnosis of a complex chronic condition, surgery, or ICU (PICU) admission. Micronutrient supplements, nonopioid analgesics, cathartics, laxatives, and antibiotics were excluded in primary analyses. RESULTS: Medication counts at discharge were 1.27-fold (95% confidence interval [CI]: 1.25-1.29) greater than admission. The change in medications at discharge (versus admission) was increased by younger age, absence of a complex chronic condition, surgery, PICU admission, and discharge from a surgical service. The most common drug subclasses at discharge were opioids (22% of discharges), proton pump inhibitors (18%), bronchodilators (10%), antiemetics (9%), and corticosteroids (9%). Postsurgical patients had higher RRs of opioid prescriptions at discharge (versus admission; RR: 13.3 [95% CI: 11.5-15.3]) compared with nonsurgical patients (RR: 2.38 [95% CI: 2.22-2.56]). CONCLUSIONS: Pediatric inpatients were discharged from the hospital with more medications than admission, frequently with drugs that may be discretionary rather than essential. The high frequency of opioid prescriptions in postsurgical patients is a priority target for educational and clinical decision support interventions.

Population Pharmacokinetic Models of Vancomycin in Paediatric Patients: A Systematic Review.

BACKGROUND: Vancomycin is commonly used to treat gram-positive bacterial infections in the paediatric population, but dosing can be challenging. Population pharmacokinetic (popPK) modelling can improve individualization of dosing regimens. The primary objective of this study was to describe popPK models of vancomycin and factors that influence pharmacokinetic (PK) variability in paediatric patients. METHODS: Systematic searches were conducted in the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, International Pharmaceutical Abstracts and the grey literature without language or publication status restrictions from inception to 17 August 2020. Observational studies that described the development of popPK models of vancomycin in paediatric patients (< 18 years of age) were included. Risk of bias was assessed using the National Heart, Lung and Blood Institute Study Quality Assessment Tool for Case Series Studies. RESULTS: Sixty-four observational studies (1 randomized controlled trial, 13 prospective studies and 50 retrospective studies of 9019 patients with at least 25,769 serum vancomycin concentrations) were included. The mean age was 2.5 years (range 1 day-18 years), serum creatinine was 47.1 ± 33.6 µmol/L, and estimated creatinine clearance was 97.4 ± 76 mL/min/1.73m2. Most studies found that vancomycin PK was best described by a one-compartment model (71.9%). There was a wide range of clearance and volume of distribution (Vd) values (range 0.014-0.27 L/kg/h and 0.43-1.46 L/kg, respectively) with interindividual variability as high as 49.7% for clearance and 136% for Vd, proportional residual variability up to 37.5% and additive residual variability up to 17.5 mg/L. The most significant covariates for clearance were weight, age, and serum creatinine or creatinine clearance, and weight for Vd. Variable dosing recommendations were suggested. CONCLUSION: Numerous popPK models of vancomycin were derived, however external validation of suggested dosing regimens and analyses in subgroup paediatric populations such as dialysis patients are still needed before a popPK model with best predictive performance can be applied for dosing recommendations. Significant intraindividual and interindividual PK variability was present, which demonstrated the need for ongoing therapeutic drug monitoring and derivation of PK models for vancomycin for certain subgroup populations, such as dialysis patients.

Pharmacokinetics of Vancomycin in Pediatric Patients Receiving Intermittent Hemodialysis or Hemodiafiltration.

INTRODUCTION: Vancomycin is a common antibiotic used to treat hemodialysis (HD) or hemodiafiltration (HDF)-related infections in pediatric patients, but optimal dosing remains unknown. This is the first observational study to characterize the pharmacokinetics and evaluate dosing of vancomycin in this population. METHODS: Eligible patients received IV vancomycin 10 mg/kg per dose postdialysis followed by a series of serum vancomycin concentrations collected before, immediately after, 1 hour after, and 4 hours after dialysis. The pharmacokinetic parameters were estimated using 1- and 2-compartment models and a nonlinear least-squares algorithm. RESULTS: Among 42 vancomycin courses in 16 patients, 1 compartment model had the best fit for observed data. The net drug removal was 43 ± 13% (39% for HD and 50% for HDF) from an average 3-hour HD/HDF session. The mean elimination constant was 0.28 h-1 (standard deviation [SD], 0.11 h-1) during the intradialytic period compared with 0.0049 h-1 (SD, 0.004 h-1) when off dialysis. The mean volume of distribution was 0.65 (SD, 0.19) L/kg. Duration of dialysis session and mode of dialysis (HD vs. HDF) were significant predictors of vancomycin pharmacokinetic parameters. Half-life was shorter for HDF compared with HD (2.1 vs. 3.5 hours). CONCLUSIONS: Based on the simulations, an initial vancomycin dose of 10 mg/kg per dose and redosing postdialysis was optimal to achieve a vancomycin concentration range of 5 to 12 mg/L at 4 hours postdialysis and 24-hour area under the curve over minimum inhibitory concentration of ≥400 hours. Therapeutic drug monitoring is necessary to account for residual variability in vancomycin elimination in pediatric patients receiving HD/HDF.

Testing for non-inferior mortality: a systematic review of non-inferiority margin sizes and trial characteristics.

OBJECTIVE: To describe the size and variability of non-inferiority margins used in non-inferiority trials of medications with primary outcomes involving mortality, and to examine the association between trial characteristics and non-inferiority margin size. DESIGN: Systematic review. DATA SOURCES: Medline, Medline In Process, Medline Epub Ahead of Print and Embase Classic+Embase databases from January 1989 to December 2019. ELIGIBILITY CRITERIA: Prospective non-inferiority randomised controlled trials comparing pharmacological therapies, with primary analyses for non-inferiority and primary outcomes involving mortality alone or as part of a composite outcome. Trials had to prespecify non-inferiority margins as absolute risk differences or relative to risks of outcome and provide a baseline risk of primary outcome in the control intervention. RESULTS: 3992 records were screened, 195 articles were selected for full text review and 111 articles were included for analyses. 82% of trials were conducted in thrombosis, infectious diseases or oncology. Mortality was the sole primary outcome in 23 (21%) trials, and part of a composite primary outcome in 88 (79%) trials. The overall median non-inferiority margin was an absolute risk difference of 9% (IQR 4.2%-10%). When non-inferiority margins were expressed relative to the baseline risk of primary outcome in control groups, the median relative non-inferiority margin was 1.5 (IQR 1.3-1.7). In multivariable regression analyses examining the association between trial characteristics (medical specialty, inclusion of paediatric patients, mortality as a sole or part of a composite primary outcome, presence of industry funding) and non-inferiority margin size, only medical specialty was significantly associated with non-inferiority margin size. CONCLUSION: Absolute and relative non-inferiority margins used in published trials comparing medications are large, allowing conclusions of non-inferiority in the context of large differences in mortality. Accepting the potential for large increases in outcomes involving mortality while declaring non-inferiority is a challenging methodological issue in the conduct of non-inferiority trials.

Pharmacotherapy in Critically Ill Children: A Retrospective Review of 17,199 Admissions.

OBJECTIVES: Despite the ubiquitous role of pharmacotherapy in the care of critically ill children, descriptions of the extent of pharmacotherapy in critical illness are limited. Greater understanding of drug therapy can help identify clinically important associations and assist in the prioritization of efforts to address knowledge gaps. The objectives of this study were to describe the diversity, volume, and patterns of pharmacotherapy in critically ill children. DESIGN: A retrospective cohort study was performed with patient admissions to the ICU between July 31, 2006, and July 31, 2015. SETTING: The study took place at a single, free-standing, pediatric, quaternary center. PATIENTS: Eligible patient admissions were admitted to the ICU for more than 6 hours and received one or more drug administration. There were a total 17,482 patient-admissions and after exclusion of 283 admissions (2%) with no documented enteral or parenteral drug administration, 17,199 eligible admissions were studied. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The 17,199 eligible admissions were admitted to the ICU for 2,208,475 hours and received 515 different drugs. The 1,954,171 administrations were 894,709 (45%) enteral administrations, 998,490 (51%) IV injections and 60,972 (3%) infusions. Infusions were administered for 4,476,538 hours. Twelve-thousand two-hundred seventy-three patients (71%) were administered five or more different drugs on 80,943 of patient days (75%). The 10 most commonly administered drugs comprised of 834,441 administrations (43%). CONCLUSIONS: Drug administration in the ICU is complex, involves many medications, and the potential for drug interaction and reaction is compounded by the volume and diversity of therapies routinely provided in ICU. Further evaluation of polytherapy could be used to improve outcomes and enhance the safety of pharmacotherapy in critically ill children.

Stress Ulcer Prophylaxis in Critically Ill Children: A Multicenter Observational Study.

OBJECTIVE: To describe current stress ulcer prophylaxis practice in Canadian PICUs. DESIGN: Multicenter cohort study. We defined stress ulcer prophylaxis as the use of a proton-pump inhibitor, histamine-2 receptor antagonist, or sucralfate within the first 2 PICU days among children who had not been on these medications at home and had no evidence of gastrointestinal bleeding. SETTING: Seven PICUs in Canada. PATIENTS: Three hundred seventy-eight children requiring mechanical ventilation. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Children were ventilated for a median (interquartile range) of 2 days (1-6 d) and stayed in the PICU for a median (interquartile range) of 4 days (2-10 d). The median (interquartile range) age was 1.3 years (0.3-6.7 yr). Seventy percent of all children received acid suppression during their PICU stay. One hundred sixty-seven (54%) of the 309 children eligible for stress ulcer prophylaxis received it. Histamine-2 receptor antagonists were the most frequently used class (66%), followed by proton-pump inhibitors (47%) and sucralfate (4%), and 20% received more than one class. Stress ulcer prophylaxis was continued on the PICU transfer orders for 34% of these children. Children who received prophylaxis were older and had a higher Pediatric Risk of Mortality III score, more often received nonsteroidal anti-inflammatory drugs and systemic corticosteroids and received less enteral nutrition. In multivariate analysis, age and invasive mechanical ventilation were independently associated with an increased likelihood of receiving stress ulcer prophylaxis and receiving feeds was independently associated with a decreased likelihood of receiving stress ulcer prophylaxis. Gastrointestinal bleeding was reported in 21 (6%) of 378 children; three (0.8%) were clinically important. Eighteen percent were treated for a new respiratory tract infection, and 1% developed Clostridium difficile-associated diarrhea. CONCLUSIONS: Stress ulcer prophylaxis is common in Canadian PICUs. Clinically important gastrointestinal bleeding and C. difficile-associated diarrhea are rare, and the utility of routine prophylaxis should be examined.

Optimizing gentamicin conventional and extended interval dosing in neonates using Monte Carlo simulation - a retrospective study.

BACKGROUND: Although aminoglycosides are routinely used in neonates, controversy exists regarding empiric dosing regimens. The objectives were to determine gentamicin pharmacokinetics in neonates, and develop initial mg/kg dosing recommendations that optimized target peak and trough concentration attainment for conventional and extended-interval dosing (EID) regimens. METHODS: Patient demographics and steady-state gentamicin concentration data were retrospectively collected for 60 neonates with no renal impairment admitted to a level III neonatal intensive care unit. Mean pharmacokinetics were calculated and multiple linear regression was performed to determine significant covariates of clearance (L/h) and volume of distribution (L). Classification and regression tree (CART) analysis identified breakpoints for significant covariates. Monte Carlo Simulation (MCS) was used to determine optimal dosing recommendations for each CART-identified sub-group. RESULTS: Gentamicin clearance and volume of distribution were significantly associated with weight at gentamicin initiation. CART-identified breakpoints for weight at gentamicin initiation were: ≤ 850 g, 851-1200 g, and > 1200 g. MCS identified that a conventional dose of gentamicin 3.5 mg/kg given every 48 h or an EID of 8-9 mg/kg administered every 72 h in neonates weighing ≤ 850 g, and every 24 and 48 h, respectively, in neonates weighing 851-1200 g, provided the best probability of attaining conventional (peak: 5-10 mg/L and trough: ≤ 2 mg/L) and EID targets (peak:12-20 mg/L, trough:≤ 0.5 mg/L). Insufficient sample size in the > 1200 g neonatal group precluded further investigation of this weight category. CONCLUSIONS: This study provides initial gentamicin dosing recommendations that optimize target attainment for conventional and EID regimens in neonates weighing ≤ 1200 g. Prospective validation and empiric dose optimization for neonates > 1200 g is needed.

Choosing medications wisely: Is it time to address paediatric polypharmacy?

There is a growing focus in the medical community on de-escalating medical treatments where appropriate; however, specific efforts to reduce medication burden in patients with polypharmacy has largely been targeted toward adult populations. Polypharmacy increases the risk of adverse drug reactions in children, and that risk may be further increased by the use of off-label drugs. The paediatric prescribing community should explore pharmacovigilance strategies and deprescription initiatives that prioritize patients with polypharmacy. Currently, best practices may be extrapolated from the adult literature, including medication review algorithms and patient education tools. Enhancing access to nonpharmacological modalities to address child and youth mental health may mitigate psychotropic polypharmacy. The aim of these initiatives should be to improve patient outcomes and experiences by avoiding adverse drug events and drug-drug interactions.

Relationship between cyclosporine area-under-the curve and acute graft versus host disease in pediatric patients undergoing hematopoietic stem cell transplant: A prospective, multicenter study.

Traditionally in hematopoietic stem cell transplant (HSCT), cyclosporine doses are individualized using cyclosporine trough concentrations (C0) while area under the concentration vs time curve (AUC) is used in solid organ transplant. AUC potentially has an important relationship with the development of acute graft-versus-host-disease (aGVHD). We conducted a prospective study to describe the relationship between severe (grade III-IV) aGVHD and cyclosporine AUC in pediatric HSCT recipients. Pediatric patients who underwent allogeneic myeloablative HSCT and scheduled to receive cyclosporine for aGVHD prophylaxis participated in this multicenter study. Cyclosporine doses were adjusted based on C0 according to each center's standard of care. Cyclosporine AUC was determined weekly until neutrophil engraftment or Day +42, whichever was later. Associations between severe aGVHD and cyclosporine AUC and other patient and treatment-related factors were evaluated. Of the 110 children enrolled, 97 were evaluable. Thirty-seven (38%) children developed aGVHD; 13 (13.4%) had severe aGVHD. On univariate analysis, there was no association between severe aGVHD and cyclosporine AUC at any time point before engraftment. Future research should focus on refinement of C0 targets for cyclosporine therapeutic drug monitoring in HSCT.

Concurrent intravenous drug administration to critically ill children: Evaluation of frequency and compatibility.

PURPOSE: To evaluate the frequency of concurrent drug administration and drug-drug incompatibility of concurrently administered drugs in critically ill children based on available references. MATERIALS AND METHODS: We retrospectively evaluated concurrent intravenous drug administration in children admitted to a single centre. Eligible patients included those admitted to the critical care unit for at least 6-hours in the ten-year period ending 30 July 2015 and received two or more IV drug administrations. Compatibilities were classified using local reference documents. RESULTS: The 16,863 eligible patients were admitted to ICU for 2,212,326h and received 3,664,667 concurrent administrations. Concurrent infusions ran for 6,263,600h. There were 2,284,066 (62%) concurrent administrations; 334,144 (9%) were compatible, 293,856 (8%) were incompatible, 293,856 (8%) required pharmacist consultation, and 752,601 (21%) had 'unknown' compatibility. Individual patients received a median (IQR) of 33 (10-132) concurrent administrations, comprised of 7 (1-30) concurrent injections 1 (0-5) concurrent infusions and 13 (0-74) concurrently administered injections and infusions. CONCLUSIONS: Concurrent IV-drug administration is frequent in critically ill children. Known incompatible concurrent administration occurs, however the compatibilities of many drug-drug pairs were unknown - adding complexity to routine bedside management and identifying information gaps for future research.

A prospective study evaluating tobramycin pharmacokinetics and optimal once daily dosing in burn patients.

BACKGROUND: Once-daily aminoglycoside dosing (ODA) is used in most patient populations to optimize antibacterial activity and reduce toxicity. Unfortunately, burn patients are excluded from ODA due to concerns over altered pharmacokinetics resulting in a shortened half-life and low peak aminoglycoside concentrations. Retrospective studies suggest that ODA may be appropriate if higher milligram/kilogram doses are used. However, no prospective clinical trials in burn patients exist to confirm these findings. OBJECTIVE: To determine the adequacy of once daily tobramycin dosed at 10mg/kg in adult burn patients. METHODS: This prospective single dose pharmacokinetic clinical trial was conducted at the Ross Tilley Burn Centre. Patients with a total burn surface area (TBSA) of <20% and creatinine clearance ≥50mL/min were eligible. A first-order one compartment model was used to determine the pharmacokinetic profile from 3 or 5 tobramycin levels over a 24h period per patient. Monte Carlo simulation (MCS) was performed to determine the probability of target level attainment. RESULTS: The mean percent TBSA, partial, and full thickness burn were 10%, 6%, and 4%, respectively. Nine of the ten patients recruited achieved peak concentrations of ≥20mg/L (mean of 29.4±5.7mg/L) and all patients had a trough level ≤0.5mg/L. The mean half-life, volume of distribution, and clearance were 2.58h, 0.33L/kg, and 7.40L/h, respectively. The MCS determined probability of attaining target peak concentrations with the 10mg/kg dose was 97%, which almost doubled that predicted with the usual 7mg/kg dose. CONCLUSION: Burn patients with adequate renal function and <20% TBSA are candidates for ODA. Tobramycin half-life was similar to healthy, non-burn patients. The larger than normal volume of distribution supports the use of the higher empiric dose of 10mg/kg total body or adjusted weight in non-obese and obese patients, respectively, with further dose adjustment based on therapeutic drug monitoring.

Nevirapine Pharmacokinetics and Safety in Neonates Receiving Combination Antiretroviral Therapy for Prevention of Vertical HIV Transmission.

BACKGROUND: Nevirapine (NVP)-based combination antiretroviral therapy is routinely prescribed to infants deemed at high risk of vertical HIV infection in our centers. We evaluated NVP pharmacokinetics and safety of this regimen. METHODS: Neonates were recruited prospectively between September 2012 and April 2015 or enrolled retrospectively if treated similarly before prospective study initiation. NVP was dosed at 150 mg/m daily for 14 days, then twice daily for 14 days. NVP levels were drawn at weeks 1, 2, and 4 [target trough (NVP-T): 3-8 mg/L]. RESULTS: Thirty-three neonates were included (23 prospectively). Median gestational age (GA) and birth weight were 38 weeks (32-41 weeks) and 2.9 kg (1.5-4.2 kg), respectively. Median NVP-Ts were 8.2 mg/L (1.6-25.1 mg/L), 3.5 mg/L (1.6-6.8 mg/L), and 4.3 mg/L (0.1-19.9 mg/L) at weeks 1, 2, and 4, respectively. The proportions with therapeutic NVP-T were 42%, 61%, and 73% at these same timepoints. Median apparent oral clearance (CL/F) increased from 0.05 L·kg·h (0.01-0.50 L·kg·h) at week 2 to 0.18 L·kg·h (0.01-0.78 L·kg·h) at week 4. Increased drug exposure [area under the curve (AUCτ)] correlated with younger GA (r = 0.459, P = 0.032) and lower birth weight (r = 0.542, P = 0.009). The most common adverse events potentially attributable to combination antiretroviral therapy were transient asymptomatic hyperlactatemia (26%), anemia (24.7%), and neutropenia (22.1%). CONCLUSIONS: Treatment dose NVP was generally well-tolerated and associated with normalization of trough levels over time in most cases without dose adjustment. Lower empiric dosing is recommended for infants <34 weeks of GA. Routine therapeutic drug monitoring may not be required for infants ≥34 weeks of GA.

Prolonged Dexmedetomidine Infusion and Drug Withdrawal In Critically Ill Children.

OBJECTIVE: To characterise the incidence, symptoms and risk factors for withdrawal associated with prolonged dexmedetomidine infusion in paediatric critically ill patients. METHODS: Retrospective chart review in the paediatric intensive care unit and the cardiac critical care unit of a single tertiary children's hospital. Patients up to 18 years old, who received dexmedetomidine for longer than 48 hours were included. RESULTS: A total of 52 patients accounted for 68 unique dexmedetomidine treatment courses of more than 48 hours. We identified 24 separate episodes of withdrawal in the 68 dexmedetomidine courses (incidence 35%). Of these episodes 38% occurred in patients who were weaned from dexmedetomidine alone while the remaining occurred in patients who had concurrent weans of opioids and/or benzodiazepines. Most common symptoms were agitation, fever, vomiting/retching, loose stools and decreased sleep. The symptoms occurred during the latter part of the wean or after discontinuation of dexmedetomidine. A cumulative dose of dexmedetomidine of 107 mcg/kg prior to initiation of wean was more likely associated with withdrawal (this equates to a dexmedetomidine infusion running at 1 mcg/kg/hr over 4 days). Duration of opioid use was an additional risk factor for withdrawal. The use of clonidine, as a transition from dexmedetomidine, did not protect against withdrawal (p = 1). CONCLUSIONS: A withdrawal syndrome may occur after prolonged infusion of dexmedetomidine. As all our patients were also exposed to opioids this may be affected by the duration of opioid use. We identified a cumulative dose of 107 micrograms/kg of dexmedetomidine beyond which withdrawal symptoms were more likely (which equates to 4 days of use at a dose of 1 mcg/kg/hr). A protocol for weaning should be considered in this circumstance.