Clinical evaluation of an authorized medical equipment based on high performance liquid chromatography for measurement of serum voriconazole concentration.

BACKGROUND: Therapeutic drug monitoring for voriconazole is recommended for its optimum pharmacotherapy. Although the feedback of the measurement result of serum voriconazole concentration by outsourcing needs a certain time (days within a 1 week), there was no medical equipment for the measurement available in clinical practice. Recently, a medical equipment based on high performance liquid chromatography, named LM1010, has been developed and authorized for clinical use. In this study, to validate the clinical performance of LM1010, we compared the measured serum voriconazole concentrations by LM1010 with those by outsourcing measurement using liquid chromatography-tandem mass spectrometry. METHODS: We conducted the observational study approved by the institutional review board of Kumamoto University Hospital (No. 1786). Residual serum samples harvested for therapeutic drug monitoring were separated. Measured concentrations by LM1010 by the standard filter method (needs serum volume of > 400 µL) or the dilute method (needs serum volume of 150 µL) were compared with those by outsourcing, respectively. Acceptable measurement error range of 0.72-1.33 was considered. There were 69 serum samples, where the 35 or 34 samples were employed for evaluation of the standard filter method or the dilute method, respectively. RESULTS: The measured concentration using the standard filter method/outsourcing was 2.22/2.10 µg/mL as the median, 1.57-3.40/1.53-3.62 as the interquartile range, < 0.2-10.76/< 0.2-11.46 µg/mL as the range, while those using the dilute method/outsourcing was 2.36/2.29 µg/mL as the median, 1.08-2.94/1.03-3.06 as the interquartile range, 0.24-10.00/< 0.2-10.85 µg/mL as the range. The regression line for the standard filter method or the dilute method were y = 0.935x + 0.154 or y = 0.933x + 0.162, respectively. The standard filter method or the dilute method showed 11.4% samples (4/35, 95%CI 3.2-26.7%) or 8.8% samples (3/34, 95%CI 1.9-23.7%) out of the acceptable measurement error range, respectively. CONCLUSION: Measurement of serum voriconazole concentration by LM1010 can be acceptable in clinical TDM practice.

A case of recovery from aphasia following dose reduction of cefepime by bayesian prediction-based therapeutic drug monitoring.

Cefepime is known to exert bactericidal activity against Pseudomonas aeruginosa. Cefepime-induced neurotoxicity, most likely caused by increased exposure, has recently become a major concern in clinical practice; therefore, appropriate dose reduction of cefepime should be applied with respect to patients with low cefepime clearance (mostly eliminated by the kidneys). Here, we report a case in which Bayesian prediction-based therapeutic drug monitoring (Bayes-TDM) was effectively used to reduce the dose of cefepime in a patient with pneumonia to prevent neurotoxic complications. A woman (age: 59 years, body weight: 32.5 kg, serum creatinine concentration: 1.02 mg/dL) developed pneumonia caused by P. aeruginosa while receiving treatment for scleroderma and systemic lupus erythematosus. She started treatment with a dosing regimen of 1.0 g of cefepime every 8 h (day X). On day X+5, aphasia developed, and the serum cefepime concentration was 71.3 mg/L at trough. This concentration was twice or thrice higher than the reported safe concentration of cefepime (22 or 35 mg/L at trough). Therefore, we reduced the dose of cefepime to 0.5 g every 12 h using Bayes-TDM from day X+7. As a result, the severity of aphasia decreased by day X+10, and this dose was successfully continued up to day X+13 without further adjustment. In conclusion, individualizing doses by Bayes-TDM may be useful in preventing adverse effects associated with cefepime treatment.

Development and evaluation of a vancomycin dosing nomogram to achieve the target area under the concentration-time curve. A retrospective study.

Although the superiority of vancomycin dosing based on area under the concentration-time curve (AUC0-24) over that based on trough concentration has been reported, a dosing strategy to achieve the target AUC0-24 has yet to be developed. The objective of this study was to develop a convenient useable nomogram for vancomycin dosing to obtain the target AUC0-24 (400 µg h/mL). The nomogram was pharmacokinetically developed in a retrospective manner. The number of enrolled patients and concentrations was 166 and 309 for development of the nomogram, 99 and 181 for evaluation of the nomogram, respectively. The nomogram was developed as doses per personal body weight corresponding to each range of estimated glomerular filtration rate (eGFR), which was identified to be the covariate for vancomycin clearance by non-linear mixed effect modeling. The nomogram described the surrogate trough concentration for the target AUC0-24 was calculatedly different for each eGFR range (9.3-15.0 µg/mL). The rate of attainment of therapeutic range using surrogate trough concentration to obtain the target AUC0-24 was 63.8% in the evaluation period. We have developed and evaluated the first convenient useable nomogram of vancomycin dosing to obtain the target AUC0-24.

Continuous high-dose infusion of doripenem in a pneumonia patient infected by carbapenem-resistant Pseudomonas aeruginosa: a case report.

BACKGROUND: Despite the high mortality of patients with sepsis and carbapenem-resistant bacteria infection, appropriate antimicrobial therapies are yet to be established. Here, we have reported the case of a patient with pneumonia that subsequently developed by carbapenem-resistant Pseudomonas aeruginosa infection and was treated with a continuous high-dose infusion of doripenem. CASE PRESENTATION: We started a continuous intravenous infusion of doripenem 3 g/day although the 59-year-old woman (body weight, 45 kg) had developed septic acute kidney injury, followed by continuous renal replacement therapy (the effluent flow rate was 650 mL/h). The minimum inhibitory concentration (MIC) of doripenem was 8 mg/L. The concentration of unbound doripenem in the serum was measured by using high-performance liquid chromatography. Twenty hours after the initial dose, the patient's serum level of doripenem was 47.8 µg/mL; the level decreased to 33.6 µg/mL at 111 h after initial dosing. The unbound doripenem concentration in the serum was maintained four times above the MIC throughout the treatment. After the completion of 11 days of dosing, the patient was discharged from the intensive care unit. During the treatment period, the MIC remained at 8 mg/L. CONCLUSIONS: A continuous high-dose infusion of doripenem is a potentially efficient strategy for the treatment of antimicrobial-resistant bacteria. Moreover, therapeutic drug monitoring may be useful for patients displaying variable pharmacokinetics, because the MIC is generally high in resistant bacteria.

Control of postprandial hyperglycaemia by galactosyl maltobionolactone and its novel anti-amylase effect in mice.

The ability to control carbohydrate digestion is useful in the treatment of diabetes mellitus and obesity. In the present study, we examined whether recently developed 4(2)-O-beta-D-galactosyl maltobionolactone (LG2O) having anti-amylase activity is able to control postprandial blood glucose concentration in mice. In addition, we tried to determine how LG2O regulates carbohydrate delivery in the gut lumen by conducting in vivo and in vitro studies. Male non-diabetic ddY mice and KK-A(y) mice, a spontaneously diabetic strain, had free access to a carbohydrate rich diet supplemented with LG2O (3 or 10 g/kg) for 0.5 hr, and blood glucose concentration was measured. LG2O suppressed any steep increase in postprandial blood glucose concentration in both ddY and KK-A(y) mice. Corresponding to the blood glucose response, LG2O also markedly suppressed any increase in postprandial plasma insulin concentration. After ingestion of the diet, LG2O produced a 1.5-3.5 fold increase in the gut contents and reducible sugar content in the small intestine but not in the stomach. Although alpha-amylase activity in the stomach was much lower compared with the activity in the small intestine, LG2O still strongly inhibited alpha-amylase activity in the stomach. In contrast, LG2O had little or no influence on alpha-amylase activity in the proximal intestine. From the in vitro carbohydrate digestion stimulation, LG2O at 7.5 mM decreased glucose production by 75% for dextrin, 25% for alpha-starch and 60% for raw starch. In conclusion, administration of LG2O inhibits carbohydrate digestion in the gut, and produces significant improvements in both blood glucose and insulin response following ingestion as part of the diet, and this evidence provides support for its therapeutic potential in treating diabetes mellitus and obesity.