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].).

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.

The use of hypnosedative drugs in a university hospital: has anything changed in 10 years?

AIM: Our goal was to investigate the use of hypnosedatives (HSs) before and during hospitalization, explore the relationship between their use and various demographic and clinical variables, and compare the results with data from a similar 2000 study with particular interest in adherence to hospital formulary guidelines. METHODS: A cross-sectional observational survey of 326 hospitalized patients recruited from ten wards of the Ghent University Hospital, Gent, Belgium, with a patient interview and by evaluating medical and nursing files. RESULTS: In 30.7% of patients, the use of a HS before admission was reported. According to the patient interview, 33.1% used a HS during hospitalization. However, according to medical and nursing files, use of HSs in the hospital was 10% higher (43.3%). In 19.4% of patients who took HSs before admission, their use was discontinued in the hospital. In 15.6% of patients who took no HS before admission, a HS was started in the hospital, according to the formulary guidelines (data from files). There was a positive correlation between HS use in the hospital and older age, longer hospitalization, not coming from home, higher number of HSs taken before hospitalization, sleeping problems emerging during hospitalization, and central nervous system (CNS) disorders. In comparison with 2000, we registered a slight decrease in HS use during hospitalization and a decrease in the number of newly started patients. CONCLUSIONS: The prevalence of HS use in our university hospital is high, mostly as a result of continuation of HSs started before admission, as there seems to be no general policy of active cessation. Compared with the survey performed 10 years ago, fewer hospitalized patients are newly started on HSs, and when this is the case, the formulary guidelines are followed.

Hemifacial paralysis in a child treated for leukemia: unusual side effect of omeprazole?

We report a hemifacial paralysis as an adverse drug reaction possibly related to the use of omeprazole in a patient with acute lymphoblastic leukemia. We believe that this case, although very rare, is clinically significant and worth mentioning, owing to the frequent use of omeprazole in the oncology setting.

Gastric ulcer in a child treated with deferasirox.

We present a patient with thalassemia major who developed a gastric ulcer, probably related to the use of deferasirox. Although gastric ulcer is mentioned as infrequent adverse event in the scientific product information of deferasirox, in our current knowledge, this is the first case-report on this adverse drug reaction. The severity of this event justifies the reporting of this case.

Implementation of guidelines for sequential therapy with fluoroquinolones in a Belgian hospital.

OBJECTIVE: This study measured the impact of three interventions for physicians, in order to implement guidelines for sequential therapy (intravenous to oral conversion) with fluoroquinolones. SETTING: A Belgian university hospital with 1,065 beds. Method The first intervention consisted of the hospital-wide publication of guidelines in the local drug letter towards all prescribers. The consumption of fluoroquinolones was measured by means of an interrupted time-series (ITS) analysis 21 months before (period A) and 24 months after publication (period B). The second intervention was an educational interactive session, by infectious disease specialists, to the medical staff of orthopaedics and endocrinology. The third intervention comprised a proactive conversion programme on the abdominal surgery, gastro-enterology and plastic surgery wards, where pharmacists attached a pre-printed note with a suggestion to switch to an oral treatment every time a patient met the criteria for switching. The second and third intervention took place 6 months after the first intervention. Fluoroquinolone treatments were evaluated during a 2 month period before (group 1) and after the introduction of the second (group 2) and third (group 3) intervention. MAIN OUTCOME MEASURE: The monthly ratio of intravenous versus total fluoroquinolone consumption (daily defined doses per 1,000 bed days) was measured to assess the impact of the first intervention. The impact of the second and third intervention was measured in relation to the number of days that intravenous therapy continued beyond the day that the patient fulfilled the criteria for sequential therapy and the antibiotic cost. RESULTS: The ITS demonstrated a reduction of 3.3% in the ratio of intravenous versus total consumption after the publication of the guidelines (P = 0.011). In group 1, patients were treated intravenously for 4.1 days longer than necessary. This parameter decreased in group 2 to 3.5 days and in group 3 to 1.0 day (P = 0.006). The mean additional cost for longer intravenous treatment decreased from 188.0 euro in group 1, to 103.0 euro in group 2 and 44.0 euro in group 3 (P = 0.037). CONCLUSION: This study demonstrated that active implementation of guidelines is necessary. A proactive conversion programme by a pharmacist resulted in a reduction in the duration of the intravenous treatment, and the treatment cost.

Prevention of wrong route errors in a pediatric hemato-oncology ward.

Three consecutive wrong route administration errors are described in detail and the ease by which enteral preparations can be given by the wrong route is discussed. By introducing the use of purple oral liquid dispensers in our pediatric department, we hope to prevent and reduce the risk of similar medications errors in the future and to improve patients safety.

Impact of computerized physician order entry on medication prescription errors in the intensive care unit: a controlled cross-sectional trial.

INTRODUCTION: Medication errors in the intensive care unit (ICU) are frequent and lead to attributable patient morbidity and mortality, increased length of ICU stay and substantial extra costs. We investigated if the introduction of a computerized ICU system (Centricity Critical Care Clinisoft, GE Healthcare) reduced the incidence and severity of medication prescription errors (MPEs). METHODS: A prospective trial was conducted in a paper-based unit (PB-U) versus a computerized unit (C-U) in a 22-bed ICU of a tertiary university hospital. Every medication order and medication prescription error was validated by a clinical pharmacist. The registration of different classes of MPE was done according to the National Coordinating Council for Medication Error Reporting and Prevention guidelines. An independent panel evaluated the severity of MPEs. We identified three groups: minor MPEs (no potential to cause harm); intercepted MPEs (potential to cause harm but intercepted on time); and serious MPEs (non-intercepted potential adverse drug events (ADE) or ADEs, being MPEs with potential to cause, or actually causing, patient harm). RESULTS: The C-U and the PB-U each contained 80 patient-days, and a total of 2,510 medication prescriptions were evaluated. The clinical pharmacist identified 375 MPEs. The incidence of MPEs was significantly lower in the C-U compared with the PB-U (44/1286 (3.4%) versus 331/1224 (27.0%); P < 0.001). There were significantly less minor MPEs in the C-U than in the PB-U (9 versus 225; P < 0.001). Intercepted MPEs were also lower in the C-U (12 versus 46; P < 0.001), as well as the non-intercepted potential ADEs (21 versus 48; P < 0.001). There was also a reduction of ADEs (2 in the C-U versus 12 in the PB-U; P < 0.01). No fatal errors occurred. The most frequent drug classes involved were cardiovascular medication and antibiotics in both groups. Patients with renal failure experienced less dosing errors in the C-U versus the PB-U (12 versus 35 serious MPEs; P < 0.001). CONCLUSION: The ICU computerization, including the medication order entry, resulted in a significant decrease in the occurrence and severity of medication errors in the ICU.

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.

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.

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.

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.