Therapeutic Drug Monitoring of Meropenem in Neonate with Necrotizing Enterocolitis: A Challenge.

Necrotizing enterocolitis (NEC) continues to be a major cause of neonatal morbidity and mortality. We describe the added value of therapeutic drug monitoring by presenting the case of a preterm infant with severe NEC treated with meropenem. Dosing strategy will achieve adequate patient outcome when treating pathogens with elevated MIC. As safe as meropenem is, there are not enough data for 40 mg/kg, every 8 h infused over 4 h; accordingly, strict monitoring of blood levels is mandatory. Based on our findings, a 4 h prolonged infusion of 40 mg/kg meropenem, every 8 h, will achieve an adequate patient outcome.

Dose-finding study of rivaroxaban in hemodialysis patients.

BACKGROUND: Use of vitamin K antagonists for the prevention of stroke and systemic embolism in dialysis patients with nonvalvular atrial fibrillation is controversial. However, no good alternatives presently are available. The anti-factor Xa antagonist rivaroxaban is contraindicated for lack of pharmacokinetic, pharmacodynamic, and clinical data. This study aims to characterize the pharmacokinetics/pharmacodynamics of rivaroxaban in maintenance hemodialysis patients. STUDY DESIGN: Pharmacokinetic and pharmacodynamic study. SETTING & PARTICIPANTS: 18 maintenance hemodialysis patients without residual kidney function at 2 centers. DRUG ADMINISTRATION, OUTCOMES, & MEASUREMENTS: (1) A single dose of 10mg of rivaroxaban was administered at the end of each of 3 consecutive dialysis sessions and area under the curve (AUC) and the effect on coagulation parameters were measured for 44 hours thereafter. (2) A single dose of 10mg of rivaroxaban was given 6 to 8 hours before a dialysis session and the effect of dialysis on rivaroxaban concentrations was evaluated. (3) To assess potential accumulation, 10mg of rivaroxaban was given once daily and AUC was measured during 24 hours on days 1 and 7. RESULTS: Mean AUC0-44 of rivaroxaban plasma concentrations after a single dose of 10mg was 2,072µg/L/h, mean maximum concentration was 172.6µg/L, and mean terminal elimination half-life was 8.6 hours. Dialysis had no appreciable effect on rivaroxaban plasma concentrations. Mean trough concentration after multiple daily doses of 10mg was 20.2µg/L. LIMITATIONS: Higher rivaroxaban doses and patients with substantial residual kidney function were not studied. CONCLUSIONS: A 10-mg dose of rivaroxaban in hemodialysis patients without residual kidney function results in drug exposure similar as published for 20mg in healthy volunteers. Rivaroxaban is not eliminated by dialysis. There is no accumulation after multiple daily dosing. The efficacy and safety of rivaroxaban in hemodialysis patients should be the subject of a large randomized trial.

Oral vitamin C administration increases lipid peroxidation in hemodialysis patients.

BACKGROUND: Since vitamin C (ascorbic acid, AA) deficiency is common in hemodialysis patients, systematic supplementation has been recommended. Further, vitamin C has been advocated as a potential adjuvant to erythropoietin by virtue of its capacity to improve iron utilization. However, vitamin C may have a paradoxical pro-oxidant effect in the presence of iron. METHODS: In 109 hemodialysis patients, oral vitamin C was administered at 360 and 1,500 mg/week during 3 months each, followed by a wash-out period of 3 months. RESULTS: Serum AA increased from 0.22 to 0.33 and 0.63 mg/dl after 360 and 1,500 mg/week, respectively. However, a commensurate increase of plasma malondialdehyde (MDA), a parameter of lipid peroxidation, with 9 and 26% was observed. Serum AA and plasma MDA returned to baseline after withdrawal of vitamin C. Parameters of iron status, nutrition, inflammation, dialysis efficiency and plasma lipids remained unaltered. In a stepwise multiple regression analysis, serum AA and ferritin were strong and independent predictors of MDA. CONCLUSION: Oral vitamin C supplementation in hemodialysis patients increases lipid peroxidation, especially in patients with increased serum ferritin. The potential benefits of restored vitamin C status and improved erythropoiesis may be entirely overruled by the adverse consequences of oxidative tissue injury.

Column-switching LC-MS/MS analysis for quantitative determination of testosterone in human serum.

BACKGROUND: An accurate measurement of testosterone is needed in many clinical applications for correct diagnosis and appropriate treatment. Our aim was to develop a fast and robust high-throughput LC-MSMS method for quantification of serum testosterone in women. METHODS: Testosterone was derivatized by oximation and extracted with methyl tert-butyl ether from 200 microL of serum. Further matrix elimination was achieved on-line using a column-switching LC-method. The instrumental analysis was performed on an API4000 tandem mass spectrometer equipped with an Agilent series 1312A binary pump and an Agilent series 1311A quaternary pump. The MRM transitions were 304-->124 and 304-->112 for testosterone and 307-->124 and 307-->112 for d(3)-testosterone. RESULTS: The total analysis time of the column-switching method was 3 min. Linear calibration curves were obtained in the concentration range from 0.035 nmol/L (0.01 microg/L) to 6.92 nmol/L (2 microg/L). Within-day and between-day precision, expressed as the relative standard deviation at four different concentrations ranged from 4.70% to 9.35%. Correlation with the in-house method (solvent-extraction RIA) showed r(2)=0.920. CONCLUSIONS: The presented column-switching method offers a simple, fast and economical analysis of testosterone in human serum. The procedure requires only small sample volumes and is well suited for quantification of testosterone in serum from women and children.

Quantitative determination of vigabatrin and gabapentin in human serum by gas chromatography-mass spectrometry.

BACKGROUND: Published methods for routine clinical monitoring of vigabatrin and gabapentin are often very laborious. A simple GC-MS method was developed for the simultaneous quantitative determination of vigabatrin and gabapentin in human serum. METHODS: After protein precipitation, the compounds are derivatized by methylation and analysed on a polydimethylsiloxane column using splitless injection. Cyclobarbital is used as the internal standard. To attain maximal sensitivity, detection is performed in selected ion monitoring mode. RESULTS: The method was fully validated and linear calibration curves were obtained in the concentration ranges from 5 to 80 microg/mL for vigabatrin and from 5 to 30 microg/mL for gabapentin. The within-day and day-to-day relative standard deviations at three different concentration levels were <10% and <15%, respectively. The limit of quantitation was 2 mug/mL for both compounds. CONCLUSIONS: The presented method provides high chromatographic resolution, good sensitivity and unequivocal identification potential and can be used for simultaneous analysis of both antiepileptics.