Stability Study

On study day 0, 4 mL of a 1 mg/mL solution of norepinephrine (norepinephrine bitartrate injection USP, Sandoz Canada Inc; lot 149812, expiry April 2010) was with­drawn from a vial and further diluted in a 50-mL polyvinyl chloride (PVC) minibag of 5% D5W (Baxter Corporation, Mississauga, Ontario; lot P230821, expiry June 2010) to prepare 16 minibags with nominal concentrations of 64.5 mg/L (after consideration of 4 mL of drug volume and assuming 8 mL of overfill). This procedure was repeated to prepare 16 samples containing 64.5 mg/L of norepinephrine in 50-mL PVC minibags of 0.9% NS (Hospira, Saint-Laurent, Quebec; lot 70 011 JT, expiry April 1, 2010).

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Liquid Chromatography

The liquid chromatographic system consisted of an isocratic solvent delivery pump (model P4000, Thermo Separation Products, San Jose, California), which pumped a mixture of acetonitrile (OmniSolv; EMD Chemicals Inc, Gibbstown, New Jersey) and 0.05 M phosphoric acid (catalogue no. P286; Fisher Scientific, Toronto, Ontario) containing 1 mg/mL of heptane sulfonic acid (catalogue no. H 2766, lot 61K5431; Sigma Aldrich Canada Ltd, Oakville, Ontario) through a 15 cm x 4.6 mm reversed-phase C-18, 3-pm column (Supelcosil ABZ+Plus, catalogue no. 59194; Supelco, Oakville, Ontario) at 1.0 mL/min. The ratio of acetonitrile to 0.05 M phosphoric acid was 5:95 and was held constant during each chromatographic run. The samples were introduced into the liquid chromatographic system using an autoinjector (WISP 717-Plus; Waters Scientific, Toronto, Ontario).

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INTRODUCTION

The expiry date of medications intended for IV administra­tion following reconstitution or dilution is often limited to about 24 h, even when data on extended stability exist, because of the potential for breaks in sterility and contamination of the product. However, when reconstitution and dilution are carried out in a sterile environment, based on the guidance of USP (United States Pharmacopoeia) Chapter <797> recommendations, it is entirely reasonable to assign beyond-use dates of up to 14 days for low-risk compounded sterile products. For many drugs, extending the beyond-use date may facilitate admixture in the pharmacy, reduce wastage, and result in significant cost savings.

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The limitations of this study included its retrospective and observational design. Also, the study design prevented assessment of clinical outcomes. We cannot say for certain that age was the only factor influencing the need for q8h dosing. We performed basic statistical comparisons of mean age, sex, mean serum creatinine, and mean creatinine clearance (as calculated by the modified Cockcroft—Gault formula) to assess for other potential covariates, but age and mean creatinine clearance were the only 2 variables that differed significantly between the q8h and q12h groups. Of interest was the fact that serum creatinine was not statistically or clinically different between the groups. Thus, the difference in creatinine clearance was most likely the result of age differences between the groups. This finding supports the original rationale for focusing on age rather than creatinine clearance.

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This study was undertaken to determine whether age less than 40 years predicts the need for more frequent vancomycin dosing. In the study population, patients under the age of 40 were 3 times more likely than older patients to require q8h dosing instead of q12h dosing.

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Use of an aminoglycoside was the only variable that was significantly associated with the outcome. Patients with a prescription for an aminoglycoside were more likely to receive q8h dosing than patients without such a prescription (OR 6.7, 95% CI 1.8-25; p = 0.004).
For 7 patients (5%), the vancomycin was prescribed for empiric q8h dosing, whereas 123 patients (94%) had prescrip­tions for empiric q12h dosing (Table 3). The remaining patient (1%) had a prescription for empiric q18h dosing. The average dose per interval was significantly different between the 2 groups: 1.14 g (standard deviation [SD] 0.2) per dose for controls and 1.06 g (SD 0.2) per dose for cases (p < 0.001).

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A total of 131 patients were included in the study: 58 cases in the q8h group and 73 controls in the q12h group. The authors believe that these groups represented the entire population of eligible patients during the study period, because it was not possible to identify any additional eligible patients for the time- frame in question.

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