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Objectives: To characterize the population pharmacokinetics of piperacillin and tazobactam in critically ill infants and children, in order to develop an evidence-based dosing regimen., Patients and Methods: This pharmacokinetic study enrolled patients admitted to the paediatric ICU for whom intravenous piperacillin/tazobactam (8:1 ratio) was indicated (75 mg/kg every 6 h based on piperacillin). Piperacillin/tazobactam concentrations were measured by an LC-MS/MS method. Pharmacokinetic data were analysed using non-linear mixed effects modelling., Results: Piperacillin and tazobactam blood samples were collected from 47 patients (median age 2.83 years; range 2 months to 15 years). Piperacillin and tazobactam disposition was best described by a two-compartment model that included allometric scaling and a maturation function to account for the effect of growth and age. Mean clearance estimates for piperacillin and tazobactam were 4.00 and 3.01 L/h for a child of 14 kg. Monte Carlo simulations showed that an intermittent infusion of 75 mg/kg (based on piperacillin) every 4 h over 2 h, 100 mg/kg every 4 h given over 1 h or a loading dose of 75 mg/kg followed by a continuous infusion of 300 mg/kg/24 h were the minimal requirements to achieve the therapeutic targets for piperacillin (60% f T >MIC >16 mg/L)., Conclusions: Standard intermittent dosing regimens do not ensure optimal piperacillin/tazobactam exposure in critically ill patients, thereby risking treatment failure. The use of a loading dose followed by a continuous infusion is recommended for treatment of severe infections in children >2 months of age., (© The Author 2017. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Aim: To evaluate the effectiveness of an e-learning course compared with a face-to-face lecture on medication calculation., Background: The current knowledge on medication calculation of nursing students and nurses is insufficient to provide safe care., Design: A stratified-clustered quasi-experimental study., Methods: A random selection of nursing schools were allocated to the e-learning course (intervention group) (seven schools; 189 students) or face-to-face lecture (control group) (six schools, 222 students). Students in both groups completed a validated medication calculation test (maximum score: 16) prior to the course (T0), immediately after the course (T1) and 3 months later (T2). A linear mixed model was used for data analysis., Results: Medication calculation skills improved significantly more by the face-to-face lecture than e-learning course. Students in both groups significantly improved in medication calculation skills immediately after the course (T1) and 3 months later. The results flattened at T2 with a significant decline in the intervention group between T1 and T2 and a non-significant decline in the control group. Based on a subgroup analysis, improvement in medication calculation skills at T2 could only be observed in vocational-level (sub degree) nursing students receiving a face-to-face course., Conclusions: Both medication calculation courses had a positive effect on medication calculation skills. Students receiving traditional face-to-face lecture improved significantly more than the students receiving the e-learning course., (© 2016 John Wiley & Sons Ltd.)

There is little data available to guide amoxicillin-clavulanic acid dosing in critically ill children. The primary objective of this study was to investigate the pharmacokinetics of both compounds in this pediatric subpopulation. Patients admitted to the pediatric intensive care unit (ICU) in whom intravenous amoxicillin-clavulanic acid was indicated (25 to 35 mg/kg of body weight every 6 h) were enrolled. Population pharmacokinetic analysis was conducted, and the clinical outcome was documented. A total of 325 and 151 blood samples were collected from 50 patients (median age, 2.58 years; age range, 1 month to 15 years) treated with amoxicillin and clavulanic acid, respectively. A three-compartment model for amoxicillin and a two-compartment model for clavulanic acid best described the data, in which allometric weight scaling and maturation functions were added a priori to scale for size and age. In addition, plasma cystatin C and concomitant treatment with vasopressors were identified to have a significant influence on amoxicillin clearance. The typical population values of clearance for amoxicillin and clavulanic acid were 17.97 liters/h/70 kg and 12.20 liters/h/70 kg, respectively. In 32% of the treated patients, amoxicillin-clavulanic acid therapy was stopped prematurely due to clinical failure, and the patient was switched to broader-spectrum antibiotic treatment. Monte Carlo simulations demonstrated that four-hourly dosing of 25 mg/kg was required to achieve the therapeutic target for both amoxicillin and clavulanic acid. For patients with augmented renal function, a 1-h infusion was preferable to bolus dosing. Current published dosing regimens result in subtherapeutic concentrations in the early period of sepsis due to augmented renal clearance, which risks clinical failure in critically ill children, and therefore need to be updated. (This study has been registered at Clinicaltrials.gov as an observational study [NCT02456974].)., (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)

Background: Critically ill patients are vulnerable to dosing errors. We developed an electronic Antimicrobial Dose alert based upon Creatinine clearance (ADC-alert), which gives daily antimicrobial dosing advice based upon the 24-h creatinine clearance (CLcr)., Objective: Primary objective: to verify the correctness of the ADC-alert output and its benefit for the workload of the clinical pharmacist (CP). Secondary objective to compare the ADC-alert output between patients with normal and impaired CLcr., Setting: The 36-bed surgical and medical intensive care unit (ICU) of the Ghent University Hospital, Ghent, Belgium., Method: In a single centre prospective observational 44-day study, prescriptions were reviewed by CP and compared with the ADC-alert output advice. CP workload was calculated with and without the use of the ADC-alert. Impaired renal function was defined as a CLcr < 50 mL/min for at least 1 day during antimicrobial treatment in the ICU or the need for renal replacement therapy (RRT)., Main Outcome Measures: Correct dosing recommendation by ADC-alert compared to CP review and time spent by CP with and without the ADC-alert., Results: A total of 87 patients (554 daily antimicrobial prescriptions; 435 patient days) were both screened by CP and ADC-alert. Renal function impairment occurred in 39 patients (44.8 %) with 12 patients requiring RRT. The ADC-alert gave a correct dosage advice in 483 prescriptions (87.2 %). The overall sensitivity was 77.3 %; specificity was 89.9 %. Use of the ADC-alert reduces CP workload with 76.5 % (average time spent per patient: 17 vs. 4 min). Patients with a CLcr < 50 mL/min less frequently received a correct recommendation than patients with normal CLcr (P = 0.001). This was due to configuration problems in dialysis patients., Conclusion: We developed and evaluated an electronic alert system to generate dynamic antimicrobial dose adaptation based on the daily calculation of the 24-h CLcr of ICU patients. Its use led to substantial time savings for clinical pharmacists. However, the alert advice suffered from some developmental and other flaws. Despite resolving some of these shortcomings, bedside interpretation of the results and clinical judgement remain necessary.

Rationale, Aims and Objectives: This study evaluated clinical pharmacy costs against drug costs., Method: We conducted a randomized interventional comparative trial at the surgical intensive care unit (ICU) of Ghent University Hospital, Belgium (period B: group B1 with pharmacist consultation; control group B0). We obtained before (period A) and after (period C) control groups using 1:1 propensity score matching with B1 and B0. Mean daily ICU drug costs with standard error of the mean (SEM) were compared between B1 and B0 (primary analysis) and between matched pairs (AB1, AB0, CB1 and CB0; secondary analysis). For B, we performed a 1000 bootstrapping (by resampling B1 and B0), calculated the benefit-cost ratio using pharmacy time (gross salary) as cost (euros) and drug cost savings as benefit. We performed sensitivity analysis with and without outlier drug costs (i.e. twice the standard deviation)., Perspective: Belgian health care payer., Results: In period B, 135 patients were randomized: B0, n = 60; B1, n = 75. Pharmacists provided recommendations in 148/706 (21.0%) therapies with 83.1% acceptance. Mean drug cost difference between B0 (430.6 euros, SEM 406.0) and B1 (221.2 euros, SEM 58.7) (P = 0.870) became significant after excluding outlier drug costs (B0, 184.4 euros, SEM 42.5; B1, 90.5 euros, SEM 17.7; P < 0.001). Recommendations were cost-beneficial (break-even drug costs or savings) in 53.8% of patients with a benefit-cost ratio of 25:1 (confidence interval -5:1 to 94:1). In sensitivity analysis excluding outlier drug costs, B0 costs were significantly higher than both A and C, indicating high baseline expenses in B0., Conclusions: The randomized interventional comparative trial in a small ICU patient group suggested the potential cost-benefit of clinical pharmacy on daily ICU drug costs. However, after matching, this benefit was attenuated. A final conclusion demands a larger randomized trial adopting a similar design with matched controls. Future research should include clinical impact of recommendations., (© 2014 John Wiley & Sons, Ltd.)