Dose optimization of piperacillin/tazobactam in critically ill children.

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 effectiveness of an e-learning course on medication calculation in nursing students: a clustered quasi-experimental study.

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.

Augmented renal clearance implies a need for increased amoxicillin-clavulanic acid dosing in critically ill children.

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].).

Role of an electronic antimicrobial alert system in intensive care in dosing errors and pharmacist workload.

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.

Expected net benefit of clinical pharmacy in intensive care medicine: a randomized interventional comparative trial with matched before-and-after groups.

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.

Prophylactic use of levofloxacin during medicinal leech therapy.

BACKGROUND: Medicinal leech therapy is effective in establishing venous outflow in congested flaps and replants. However, its use is also associated with infections, especially from Aeromonas species. To prevent this nosocomial infection, levofloxacin has been established as prophylaxis during leech therapy in our hospital. OBJECTIVES: To study the implementation rate of a guideline, to study the effect of levofloxacin on possible Aeromonas infections, and to evaluate the financial impact of this preventive measure. SETTING: A retrospective analysis on all patients treated with Hirudo medicinalis between July 2007 and March 2011 was performed at the Ghent University Hospital, Belgium. METHOD: A list of patients treated with leeches was retrieved from the pharmacy database. Patient characteristics, date of start and stop of leech therapy were collected. Data on routine diagnostic cultures during leech therapy, date and type of clinical sample, while cultivated micro-organism with antibiotic susceptibility were obtained from the laboratory database. MAIN OUTCOME MEASURE: percentage implementation rate of a guideline, presence of Aeromonas infections, financial impact of levofloxacin prophylaxis. RESULTS: Fifty-one patients were treated with leeches. Forty-six (90.2 %) patients were treated according the guideline. Fourteen out of 51 patients (27.5 %) were suspected for postoperative wound infections. From them, 60 clinical samples were sent for microbiological analysis. These included exudates (26.7 %), peroperative samples (5.0 %), puncture fluid (1.7 %), blood cultures (3.3 %) or smears from burns (63.3 %). No Aeromonas species were cultivated. Comparison between period before and after implementation of levofloxacin prophylaxis revealed that levofloxacin prevents colonization or infection with Aeromonas species in relation to leech therapy. The direct cost for levofloxacin prophylaxis in the current study was 2,570 euro. Based on data obtained in a previous study, we presume that a minimum cost-saving of 20,500 euro was realised during the current study period by implementation of antimicrobial prophylaxis. CONCLUSIONS: This study demonstrates successful implementation of a guideline for levofloxacin prophylaxis during leech therapy. Following its introduction, no Aeromonas species related to the use of leeches were isolated as compared to 8.5 % in the baseline period.

Emesis control by aprepitant in children and adolescents with chemotherapy.

BACKGROUND: Chemotherapy-induced nausea and vomiting (CINV) is a feared adverse reaction during cancer treatment. Aprepitant has shown to be effective for CINV in adults, but little is known on its effect in pediatrics. So far, the drug is not licensed in this population. OBJECTIVE: To investigate efficacy of aprepitant in children and young adolescents with high or moderate emetogenic courses, with uncontrollable emesis in previous cycles. METHOD: Retrospective, observational study in children and adolescents treated with aprepitant at Ghent University Hospital, Belgium. Antiemetic regimens and emesis control were analyzed. RESULTS: Twenty patient charts representing 104 chemotherapy cycles were reviewed. Complete vomiting control was observed in 10 patients (50 %), representing 89/104 (85.6 %) episodes. Incomplete vomiting control was observed in 10 patients (50 %), representing only 15 episodes (14.4 %). Of these episodes with incomplete vomiting control, 6 were in acute phase (40 %), 7 in delayed phase (46.7 %) and 2 in both acute and delayed phase (13.3 %). CONCLUSION: Aprepitant might be effective in preventing or reducing vomiting in children. When combined with standard antiemetics, aprepitant was well tolerated. In attendance of results of on-going international clinical trials, our results encourage us to continue the use of aprepitant after failure of emesis control in previous cycles.

Evaluation of clinical pharmacist recommendations in the geriatric ward of a Belgian university hospital.

OBJECTIVE: To evaluate the type, acceptance rate, and clinical relevance of clinical pharmacist recommendations at the geriatric ward of the Ghent university hospital. METHODS: The clinical pharmacist evaluated drug use during a weekly 2-hour visit for a period of 4 months and, if needed, made recommendations to the prescribing physician. The recommendations were classified according to type, acceptance by the physician, prescribed medication, and underlying drug-related problem. Appropriateness of prescribing was assessed using the Medication Appropriateness Index (MAI) before and after the recommendations were made. Two clinical pharmacologists and two clinical pharmacists independently and retrospectively evaluated the clinical relevance of the recommendations and rated their own acceptance of them. RESULTS: The clinical pharmacist recommended 304 drug therapy changes for 100 patients taking a total of 1137 drugs. The most common underlying drug-related problems concerned incorrect dose, drug-drug interaction, and adverse drug reaction, which appeared most frequently for cardiovascular drugs, drugs for the central nervous system, and drugs for the gastrointestinal tract. The most common type of recommendation concerned adapting the dose, and stopping or changing a drug. In total, 59.7% of the recommendations were accepted by the treating physician. The acceptance rate by the evaluators ranged between 92.4% and 97.0%. The mean clinical relevance of the recommendations was assessed as possibly important (53.4%), possibly low relevance (38.1%), and possibly very important (4.2%). A low interrater agreement concerning clinical relevance between the evaluators was found: kappa values ranged between 0.15 and 0.25. Summated MAI scores significantly improved after the pharmacist recommendations, with mean values decreasing from 9.3 to 6.2 (P < 0.001). CONCLUSION: In this study, the clinical pharmacist identified a high number of potential drug-related problems in older patients; however, the acceptance of the pharmacotherapy recommendations by the treating physician was lower than by a panel of evaluators. This panel, however, rated most recommendations as possibly important and as possibly having low relevance, with low interrater reliability. As the appropriateness of prescribing seemed to improve with decreased MAI scores, clinical pharmacy services may contribute to the optimization of drug therapy in older inpatients.

Augmented renal clearance is a common finding with worse clinical outcome in critically ill patients receiving antimicrobial therapy.

INTRODUCTION: We describe incidence and patient factors associated with augmented renal clearance (ARC) in adult intensive care unit (ICU) patients. MATERIALS AND METHODS: A prospective observational study in a mixed cohort of surgical and medical ICU patients receiving antimicrobial therapy at the Ghent University Hospital, Belgium. Kidney function was assessed by the 24-hour creatinine clearance (Ccr); ARC defined as at least one Ccr of >130 mL/min per 1.73 m2. Multivariate logistic regression analysis: to assess variables associated with ARC occurrence. Therapeutic failure (TF): an impaired clinical response and need for alternate antimicrobial therapy. RESULTS: Of the 128 patients and 599 studied treatment days, ARC was present in 51.6% of the patients. Twelve percent permanently expressed ARC. ARC patients had a median Ccr of 144 mL/min per 1.73 m2 (IQR 98-196). Median serum creatinine concentration on the first day of ARC was 0.54 mg/dL (IQR 0.48-0.69). Patients with ARC were significantly younger (P<.001). Age and male gender were independently associated with ARC whereas the APACHE II score was not. ARC patients had more TF (18 (27.3%) vs. 8 (12.9%); P=.04). CONCLUSION: ARC was documented in approximately 52% of a mixed ICU patient population receiving antibiotic treatment with worse clinical outcome. Young age and male gender were independently associated with ARC presence.

Epidemiology and cost analysis of pharmacist interventions at Ghent University Hospital.

BACKGROUND: Performing bedside clinical recommendations is important for the prevention of adverse drug events. From an economic perspective, the economic value of adverse drug event avoidance needs to be weighed against the labour costs of pharmacists. OBJECTIVE: To perform a cost analysis of pharmacist interventions with valproic acid, digoxin, methotrexate and penicillin. SETTING: Ghent University Hospital in Belgium (1,062-beds). METHOD: Interventions for valproic acid, digoxin, methotrexate and penicillin were selected from a clinical pharmacy database, CLINOR. The average number of registered interventions per year was 1,209 (period 2005-mid 2011). MAIN OUTCOME MEASURE: Cost difference (cost value) between that of the avoided toxicity and that of the intervention (a positive cost value is cost saving). RESULTS: Per annum, pharmacists performed interventions for valproic acid (n = 18) and digoxin (n = 21); the annual cost value of interventions for valproic acid was €18,853.7 with a standard deviation of €15,020.6; for digoxin it was €41,832.0 ± €15,348.5. With oral methotrexate, accidental toxicity occurs rarely but it can be life threatening. Two important pharmacist interventions were reported per year. The routine switching of penicillin therapy to alternative antibiotics, in patients with previous allergy, may invoke costs rather than benefits (two interventions per year). In half of cases, therapy was reinitiated without any further adverse drug event. CONCLUSION: Clinically important pharmacy interventions are not automatically cost beneficial. Interventions that prevent digoxin and valproic acid toxicity were cost effective in this setting. The routine advice to switch the antibiotic class for every reported penicillin allergy is unlikely to avoid adverse drug events and challenges the cost value of this intervention. Interventions with methotrexate are relevant because they can be lifesaving. However, due to their low incidence, effective detection of these errors is crucial for reducing harm.

Successful use of eculizumab in a pediatric patient treated for paroxysmal nocturnal hemoglobinuria.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, debilitating life-threatening clonal hematopoietic stem cell disease. The clinical manifestations of PNH are usually seen in adulthood and are very rarely reported in children. Eculizumab, a humanized monoclonal antibody targeting and preventing cleavage of the terminal complement protein C5, has become the "gold standard" of treatment for hemolysis or significant disease-related complications in patients with PNH. Although eculizumab is not licensed for use in pediatrics, we report a young PNH patient with bone marrow failure and severe episodes of hemolytic anemia who was treated successfully with eculizumab for >18 months.

What's in a drop? Optimizing strategies for administration of drugs in pediatrics.

Accurate administration of drugs is an essential part of pharmacotherapy in children. Small differences in the amount of drugs administered, might evoke different clinical effects. This is especially of concern in drugs with a narrow therapeutic index. Guided by a case that was observed in pediatrics, some practical recommendations for the administration of oral drops in children are described.

Applicability of an adapted medication appropriateness index for detection of drug-related problems in geriatric inpatients.

BACKGROUND: High drug consumption by older patients and the presence of many drug-related problems require careful assessment of drug therapy, for which a structured approach is recommended. OBJECTIVE: The purpose of our study was to evaluate the applicability of an adapted version of the Medication Appropriateness Index (MAI) in 50 geriatric inpatients at the time of admission. METHODS: We reviewed, for 432 prescribed drugs, indication, right choice, dosage, directions, drug-disease interactions, drug-drug interactions, and duration of therapy. In addition, adverse drug reactions were evaluated, resulting in 8 questions per drug. MAI scores were attributed independently by a geriatrician and by a clinical pharmacist, and differences between them were assessed. Furthermore, the relationship between MAI score and drug-related hospital admission was explored. RESULTS: Mean summed MAI scores of 13.7 according to the geriatrician and 13.6 according to the pharmacist were obtained. The highest scores were found for drugs for the central nervous and the urinary tract system; the highest scores per question were detected for right choice, adverse drug reactions, and drug-drug interactions. A good agreement between the scores of the geriatrician and the pharmacist was found: intraclass correlation coefficient was 0.91 and overall κ value was 0.71. A significantly higher MAI score was found for drug-related hospital admissions (P = 0.04 for the geriatrician and P = 0.03 for the pharmacist). CONCLUSIONS: This adapted MAI score seems useful for detection of drug-related problems in geriatric inpatients and reliable with a low inter-rater variability and positive correlation between high score and drug-related hospital admission. We consider further application of the adapted MAI for teaching and training of clinical pharmacists, and as a systematic approach for detection of drug-related problems by the clinical pharmacists in our hospital.

Stability of extemporaneously prepared cytarabine, methotrexate sodium, and methylprednisolone sodium succinate.

PURPOSE: The short-term stability of extemporaneously prepared triple intrathecal therapy, containing cytarabine, methotrexate sodium, and methylprednisolone sodium succinate, was evaluated. METHODS: Three batches of triple intrathecal solution were prepared using commercially available products and stored in three different packaging materials (plastic syringe system, brown glass vials, and brown glass vials filled with metal needles). The solutions were protected from light and stored at 5 °C, 25 °C, and 40 °C or exposed to ultraviolet and visible light at 25 °C, compliant with the International Conference on Harmonisation. Samples were taken immediately before and after 4, 8, 24, 32, and 48 hours of storage. Simultaneous high-performance liquid chromatography- ultraviolet light/diode array detector assay of cytarabine, methotrexate sodium, and methylprednisolone sodium succinate was performed using a fused-core stationary phase and an acetonitrile-based gradient. First-order kinetic degradation values were calculated, and temperature dependence was evaluated using the Arrhenius equation. RESULTS: Cytarabine was stable under all storage conditions. Methotrexate sodium displayed significant degradation after light exposure but remained stable under the other storage conditions. Methylprednisolone sodium succinate was found to be the most labile component in the triple intrathecal solution. Temperature-dependent degradation was observed, resulting in 46% degradation after 48 hours at 40 °C. Two degradants were formed: methylprednisolone and methylprednisolone hydrogen succinate. Packaging material and batch-to-batch variability did not significantly influence the stability of the triple intrathecal solution. CONCLUSION: Triple intrathecal solution of cytarabine, methotrexate sodium, and methylprednisolone sodium succinate was stable for up to 12 hours when stored at 5 °C and protected from light.

Vancomycin-induced red man syndrome in pediatric oncology: still an issue?

Red man syndrome is a rare but possibly serious adverse reaction during treatment with intravenous vancomycin. It is extremely important that pediatricians, especially in oncology, recognize this reaction and treat it appropriately. Following two case-reports from a pediatric oncology setting, a series of practical recommendations to prevent or handle red man syndrome are described.

Practical implications for the administration of 13-cis retinoic acid in pediatric oncology.

Children with high-risk neuroblastoma are treated with polychemotherapy, surgery, radiotherapy and even autologous stem-cell transplantation. On top of this complex treatment, most children also receive 13-cis retinoic acid as differentiation agent. As no suitable pharmaceutical formulation is available so far, there are often problems with the administration of the product in children. The present report describes some practical recommendations for the administration of isotretinoin in children treated for high-risk neuroblastoma.