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.

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.

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.

Dose derivation of once-daily dosing guidelines for gentamicin in critically ill pediatric patients.

OBJECTIVES: To determine dose and eligibility criteria for once-daily dosing (ODD) of gentamicin in critically ill pediatric patients. METHODS: Retrospective chart review of patients admitted to the Pediatric Intensive Care Unit or Cardiac Critical Care Unit at The Hospital for Sick Children (SickKids) who received traditionally dosed intravenous (IV) gentamicin (January 2008 to June 2010). Statistically significant patient characteristics associated with gentamicin pharmacokinetic (PK) parameters were determined by multiple linear regression. Binary partitioning was used to set critical values for these characteristics to derive dose for ODD of gentamicin. Feasibility of implementing ODD of gentamicin in critically ill children was assessed using individualized PK parameters to simulate area under the concentration-time curves and drug-free intervals while targeting a maximum concentration (C(max)) of 16-20 mg/L. Eligibility criteria were determined by patient characteristics that had a statistically significant impact on gentamicin PK. RESULTS: Volume of distribution (V(d)) and elimination rate constant (k(e)) were calculated for 140 patients. Weight and admission unit were significantly associated with weight-normalized V(d) (Vd/kg), whereas age and serum creatinine (SCr) were significantly associated with k(e). Weight <5 kg and SCr ≥20% over age-specific upper normal limit before gentamicin initiation were associated with prolonged gentamicin elimination. Gentamicin 6 mg/kg IV every 24 hours, the dose at which the highest percentage of patients achieved C(max), area under the curve, and drug-free interval within target ranges simultaneously, was selected as the proposed ODD regimen. CONCLUSIONS: A regimen of gentamicin 6 mg/kg IV every 24 hours for Pediatric Intensive Care Unit/Cardiac Critical Care Unit patients at SickKids weighing ≥5 kg with SCr <20% above age-specific upper normal limit before initiation of gentamicin is proposed.

Prediction of area under the cyclosporine concentration versus time curve in children undergoing hematopoietic stem cell transplantation.

This prospective study aimed to validate a previously developed first-dose limited sampling strategy (LSS) to predict the area under the cyclosporine concentration-versus-time curve (AUC) and to develop and then validate an LSS to predict cyclosporine AUC at steady state. This two-center Canadian study included children (ages .4 to 17.2 years) undergoing myeloablative allogeneic hematopoietic stem cell transplantation receiving cyclosporine for acute graft-versus-host disease prophylaxis. There were three cohorts, each incorporating 24 AUC determinations: first-dose LSS validation, steady-state LSS development, and steady-state LSS validation. Patients contributing data to either of the development cohorts were excluded from the corresponding validation group. Cyclosporine was given every 12 hours as a 2-hour infusion. Cyclosporine AUC was determined after administration of the first cyclosporine dose (8 samples) and then once weekly (9 samples) until engraftment. Steady-state LSSs were developed using stepwise multiple linear regression. An LSS was considered to provide an acceptable estimate of AUC if the lower limit of the 95% confidence limit (CL) of the intraclass coefficient was .8 or higher and both bias and precision were 15% or less. Fifty-three children age .4 to 18 years participated. Cyclosporine concentrations drawn up to 4 hours from the start of the infusion correlated most strongly with AUC. The previously developed first-dose LSSs and three steady-state LSSs met criteria for acceptability. The intraclass coefficients of the three-point first-dose LSS validation cohort, three-point steady-state LSS development cohort, and three-point steady-state LSS validation cohort were .974 (95% CL: .941 to .988), .984 (95% CL: .965 to .993), and .993 (95% CL: .984 to .997), respectively. The three-point first-dose (2, 6, and 8 hours) and steady-state (2, 2.5, and 8 hours) LSSs are valid measures of cyclosporine AUC after intravenous administration over 2 hours. Their use in a prospective evaluation of the relationship between cyclosporine AUC and hematopoietic stem cell transplantation clinical outcomes in children is suggested.

Point prevalence survey of antimicrobial utilization in the cardiac and pediatric critical care unit.

OBJECTIVES: To determine the rate of documented infections and prevalence of antimicrobial use among pediatric patients admitted to the PICU. To assess the appropriateness of antimicrobial prescribing according to clinical and microbiological findings, Infectious Disease Consult recommendations, and formulary guidelines. DESIGN: Prospective point prevalence study. SETTING: Cardiac and medical-surgical critical care units (CCCU-PICU) in a tertiary care pediatric teaching hospital in Toronto, Canada. PATIENTS: All patients admitted to the CCCU-PICU during the week of October 27, 2008 (period A) and February 9, 2009 (period B) were followed until completion of their antimicrobial course(s). Data were collected on infection types and indications, frequency, and types of antimicrobials used. Appropriateness of antimicrobial prescribing was assessed according to predefined criteria by four blinded clinician assessors. MEASUREMENT AND MAIN RESULTS: Forty-two of 60 patients (70%) received antimicrobials in period A and 42 of 53 patients (79%) received antimicrobials in period B. Of the patients on antimicrobials, 45% in period A and 52% in period B had a definitive diagnosis of infection. Pneumonia and sepsis were the most common infections in period A, whereas pneumonia and other respiratory tract infections were the most common in period B. Antimicrobials were commonly prescribed for documented infection (38%) during period A and empiric therapy (47%) during period B. Cefazolin, cefuroxime, vancomycin, and gentamicin were the commonly used antimicrobials during both periods. Inappropriate antimicrobial use ranged from 16.7% to 61.9%, depending on assessors and surveillance period. The most common reasons for inappropriate use were overly broad spectrum, wrong dosage, and unwarranted overlap of spectrum. CONCLUSIONS: There was a high prevalence of antimicrobial use in CCCU-PICU patients. Because a significant proportion of antimicrobial use was deemed inappropriate, interventions are required to optimize antimicrobial use in critically ill children.

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.

Therapeutic drug monitoring of voriconazole in children.

Voriconazole is an extended-spectrum triazole antifungal with activity against a wide variety of pathogens, including Aspergillus, Candida, Cryptococcus neoformans, Fusarium, and Scedosporium. It exerts its antifungal activity by blocking the synthesis of fungal cell membranes and is considered the first-line treatment for invasive aspergillosis. Because the pharmacokinetics of voriconazole can demonstrate considerable variability, it has been suggested that monitoring plasma levels of voriconazole may play an important role in optimizing the efficacy and safety of the drug in complex patients like those at risk of or who have invasive aspergillosis. In this article, we review the criteria for therapeutic drug monitoring and assess the evidence for using plasma voriconazole concentrations to individualize doses in children.

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.

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.

Drug formulations that require less than 0.1 mL of stock solution to prepare doses for infants and children.

Intravenous doses of medications require formulations that permit accurate preparation and administration. Current equipment does not permit accurate measurement of volumes less than 0.1 mL. In a study of four hypothetical standard pediatric patients, we found that 28 common medications required less than 0.1 mL of available formulation to prepare the dose. In a clinical study of actual use in a pediatric intensive care unit (ICU), 5245 (7.4%) of 71 218 intravenous doses required preparation from less than 0.1 mL of stock solution. For 28.5% of the 1531 ICU admissions, at least one dose was prepared from a volume of less than 0.1 mL. Our findings identify a substantial source of dosing error. Correction will require revision of preparation methods, regulatory requirements and manufacturing practices.

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.

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.

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.