Microcosting Study of Rituximab Subcutaneous Injection Versus Intravenous Infusion.

PURPOSE: The goal of this study is to identify and compare all direct costs of intravenous and subcutaneous rituximab given to patients with diffuse large B-cell lymphoma in the Netherlands. METHODS: Using a prospective, observational, bottom-up microcosting study, we collected primary data on the direct medical costs of the preparation, administration, and acquisition of rituximab. Drug costs and costs of drug wastage, labor costs, material costs, and outpatient costs were identified using standardized forms, structured using prices from official pricelists, and compared for the intravenous and subcutaneous forms of rituximab. FINDINGS: Measurements were taken on 53 rituximab administrations (33 intravenous and 20 subcutaneous) and on 13 rituximab preparation (7 intravenous and 6 subcutaneous). The mean total costs were €2176.77 for the intravenous infusion and €1911.09 for the subcutaneous injection. The estimated difference of €265.17 (95% CI, €231.99-`€298.35) per administration was mainly attributable to differences in time spent in the chemotherapy unit, related outpatient costs, drug wastage, and drug costs. IMPLICATIONS: Rituximab administered in the form of subcutaneous injection is less costly than its intravenous form. With their equal effectiveness taken into account, subcutaneous rituximab administration can result in significant savings when transferred to the total diffuse large B-cell lymphoma population in the Netherlands.

Targeting cefuroxime plasma concentrations during coronary artery bypass graft surgery with cardiopulmonary bypass.

BACKGOUND: Patients are at risk for severe postoperative infections after coronary artery bypass graft (CABG) surgery. Clinical laboratory data showed that unbound plasma concentrations of cefuroxime were not always adequate, therefore we developed a new dosing regimen. OBJECTIVE: The aim of this prospective study is to evaluate the new dosing strategy by monitoring patients for unbound cefuroxime plasma concentrations during CABG surgery with cardiopulmonary bypass (CPB). SETTING: A Dutch teaching hospital. METHODS: In this prospective trial, patients scheduled for CABG surgery with CPB were included. A starting dose of 1500 mg cefuroxime was given with anesthesia induction, followed by 750 mg cefuroxime every hour until wound closure. In case of renal failure the dosing regimen was adapted. Serial blood samples were collected before, during and after the CPB process. Pharmacokinetic modelling was performed by using an 'iterative two-stage Bayesian population procedure'. MAIN OUTCOME MEASURE: Unbound plasma concentrations of cefuroxime. RESULTS: 22 patients were included, data could be evaluated of 21 patients. In 24 % of the patients the unbound cefuroxime plasma concentration was below the target range during surgery before CPB started. Patients with a bodyweight above 100 kg or age <60 years were more likely to have unbound plasma concentrations below the target range (P = 0.030 and P = 0.008). During CPB, the half-life of unbound cefuroxime increased by 17 % and the clearance decreased by 11 % compared to before CPB (P = 0.033 and P = 0.014). The mean pharmacokinetic parameters before, during and after CPB were as follows: elimination half-life 72, 84 and 76 min; clearance of unbound cefuroxime (Clu) 14.2, 12.7, 13.8 l/h and volume of distribution (Vu) 0.280, 0.284 and 0.290 l/kg respectively. Variations in unbound fractions before, during and after CPB were below 2 %, implicating the unbound fraction of cefuroxime is not influenced by CPB. CONCLUSION: Our results show that CPB during CABG surgery does not lead to inadequate unbound cefuroxime concentrations. Age, renal function and possibly also weight are more important factors that can result in unbound plasma cefuroxime concentrations below the target value.

Development and validation of a liquid chromatography/tandem mass spectrometry method for the quantification of flucloxacillin and cloxacillin in microdialysis samples.

In the present study we developed and validated a liquid chromatography/tandem mass spectrometry (LC-MS/MS) assay for the determination of flucloxacillin in human plasma and microdialysis samples and cloxacillin in microdialysis samples, using oxacillin as the internal standard for the assay. The samples were separated on a UPLC BEH C18,1.7 µm column (2.1x50mm) and analyzed by a tandem-quadrupole mass spectrometer in multiple reaction monitoring mode using an electronspray ionization interface. For flucloxacillin the method was demonstrated to be accurate and precise in the linearity range of 1-30 mg/L in plasma and 0.05-5.0 mg/L for microdialysate with a regression coefficient (r) of 0.9986 and 0.9989 in plasma and microdialysate respectively. For cloxacillin it was accurate and precise in the range of 0.1-5.0 mg/L for microdialysate with a regression coefficient of 0.9972. The method presents a high sensitivity for flucloxacillin (lower limit of quantification of 1 mg/L for plasma and 0.05 mg/L for microdialysis samples) combined with a low within- and between-day variation (<5.0% for flucloxacillin and cloxacillin in microdialysis samples and <6.5% for plasma samples of flucloxacillin). The validation experiments for the microdialysis probes showed a relative recovery of 85.5% for flucloxacillin at a flow rate of 1.0 µL/min. The results justify the use of this assay for clinical studies for measuring free unbound tissue concentrations of flucloxacillin in patients with a Staphylococcus aureus bacteremia.

Adherence of antidepressants during pregnancy: MEMS compared with three other methods.

BACKGROUND: Data about adherence of antidepressants during pregnancy are lacking. However, it is important to gain insight into adherence in this population to reduce perinatal risks for relapse of depression. OBJECTIVE: The objective of this study was to search for an inexpensive and easy method to implement daily for assessing medication adherence during pregnancy. METHODS: An observational study was conducted to measure adherence by comparing pill count, Beliefs about Medicine questionnaire (BMQ) and blood level monitoring against the standard, the Medication Event Monitoring System (MEMS). We used a logistic regression model to determine potential predictors for poor adherence (age, marital class, highest level of education, monthly net income, employment, smoking, alcohol use and type of antidepressant). RESULTS: From January 2010 until January 2012, 41 women were included within the first trimester of pregnancy; data could be evaluated in 29 women. Using MEMS, 86% of the women took in more than 80% of all prescribed doses on time and could be classified as adherent. Pill counts showed good agreement with MEMS. We did not find predictors for poor adherence in our study population. CONCLUSION: Adherence of antidepressants during pregnancy using MEMS is 86%. There was a good agreement between MEMS and pill counts. This method may serve as a good alternative that can be easily implemented into daily practice.

Blood concentrations of cefuroxime in cardiopulmonary bypass surgery.

OBJECTIVES: Patients with coronary artery bypass graft (CABG) surgery are at risk for severe postoperative infections. Prophylactic cefuroxime may help to reduce this risk, however sufficient concentrations, i.e. above the breakpoint (32 mg/L), are mandatory. The aim of this study is to evaluate the blood concentrations of cefuroxime during and after CABG surgery with cardiopulmonary bypass (CPB) and hypothermia, to determine the concentration of cefuroxime in sternum fluid and to evaluate possible factors of influence. METHODS: Seventeen patients were enrolled in this study, given 1.5 g cefuroxime at anaesthesia induction and an additional 1.5 g at start CPB. Blood samples were collected at skin incision, start CPB, every 30 min on CPB, end CPB, at wound closure and 1 h after surgery. Cefuroxime concentrations were determined by high performance liquid chromatography. RESULTS: In 47 % of the patients the cefuroxime concentration was below the breakpoint at some point during the operation and in 59 % of the patients 1 h after surgery. A statistically significant inverse correlation between estimated glomerular filtration rate and plasma cefuroxime concentrations was found (P = 0.034). Cefuroxime levels in the sternum are not significantly different from blood levels from the radial artery catheter, taken at approximately the same time (P = 0.30). CONCLUSIONS: The current antibiotic regimen used did not maintain cefuroxime concentrations above the breakpoint throughout the operation, suggesting insufficient antibiotic prophylaxis. Further research to other antibiotic regimes is therefore necessary.

The effect of a multifaceted educational intervention on medication preparation and administration errors in neonatal intensive care.

OBJECTIVE: To examine the effect of a multifaceted educational intervention on the incidence of medication preparation and administration errors in a neonatal intensive care unit (NICU). DESIGN: Prospective study with a preintervention and postintervention measurement using direct observation. SETTING: NICU in a tertiary hospital in the Netherlands. INTERVENTION: A multifaceted educational intervention including teaching and self-study. MAIN OUTCOME MEASURES: The incidence of medication preparation and administration errors. Clinical importance was assessed by three experts. RESULTS: The incidence of errors decreased from 49% (43-54%) (151 medications with one or more errors of 311 observations) to 31% (87 of 284) (25-36%). Preintervention, 0.3% (0-2%) medications contained severe errors, 26% (21-31%) moderate and 23% (18-28%) minor errors; postintervention, none 0% (0-2%) was severe, 23% (18-28%) moderate and 8% (5-12%) minor. A generalised estimating equations analysis provided an OR of 0.49 (0.29-0.84) for period (p=0.032), (route of administration (p=0.001), observer within period (p=0.036)). CONCLUSIONS: The multifaceted educational intervention seemed to have contributed to a significant reduction of the preparation and administration error rate, but other measures are needed to improve medication safety further.