Yasuhiro Tsuji

University of Toyama, Тояма, Toyama, Japan

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Publications (19)39.08 Total impact

  • International Journal of Antimicrobial Agents 10/2014; · 4.26 Impact Factor
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    ABSTRACT: Linezolid has antibacterial activity against aerobic Gram-positive cocci, including methicillin-resistant Staphylococcus aureus (MRSA). Adjustment of the dose of linezolid has been proposed to be unnecessary in patients with reduced renal function. However, platelet counts and hemoglobin levels were shown to be significantly lower in such patients than in patients with normal renal function. The population pharmacokinetic (PPK) of linezolid was investigated in MRSA infected patients with renal dysfunction. Linezolid concentrations in serum were measured by high-performance liquid chromatography. PPK analysis was performed in the nonlinear mixed effects model (NONMEM) computer program. In the final PPK model, total body weight (TBW), estimated glomerular filtration rate (eGFR), hemoglobin (HB), and alanine amino transferase (ALT) were influential covariates on total body clearance (CL), and the volume of distribution (Vd) was affected by TBW, which was expressed as CL (L/h) = 0.00327 × TBW × eGFR(0.428) × HB(0.502) × 0.283 (ALT ≥ 100 IU/L) and CL (L/h) = 0.00327 × TBW × eGFR(0.428) × HB(0.502) (ALT < 100 IU/L), Vd (L) = 1.310 × TBW. The PPK parameters of linezolid obtained here are useful for the optimal use of linezolid with similar patient population characteristics.
    The Journal of Clinical Pharmacology 09/2013; 53(9):967-73. · 2.47 Impact Factor
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    ABSTRACT: The efficacy of carbapenems has been threatened by the increasing frequency of carbapenem-resistant bacteria.…
    Antimicrobial Agents and Chemotherapy 08/2013; · 4.57 Impact Factor
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    ABSTRACT: In recent years, carbapenem-resistant Acinetobacter baumannii infections have been responsible for outbreaks in medical facilities. A 35-year-old Japanese woman developed a skin and soft tissue infection due to carbapenem-resistant A. baumannii. The isolate was resistant to antibiotics other than ampicillin-sulbactam and colistin, suggesting drug resistance due to carbapenemase production by OXA-23. We selected a combination therapy consisting of intravenous ampicillin-sulbactam and meropenem. No changes were observed in aspartate aminotransferase, alanine aminotransferase, blood urea nitrogen, or serum creatinine during therapy, and carbapenem-resistant A. baumannii was not detected in wound exudates 3 days after therapy initiation. In our patient's case, combination therapy with ampicillin-sulbactam and meropenem was successful. Thus, combination therapy with ampicillin-sulbactam and meropenem is effective against skin and soft tissue infection due to carbapenem-resistant A. baumannii. Combination therapy with intravenous ampicillin-sulbactam and meropenem may be an option for skin and soft tissue infections due to carbapenem-resistant A. baumannii.
    International journal of infectious diseases: IJID: official publication of the International Society for Infectious Diseases 06/2013; · 2.17 Impact Factor
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    ABSTRACT: The purpose of this study was to investigate the penetration of linezolid into the mediastinum and pleural space by comparing its concentration in the serum, mediastinum, and pleural space. The linezolid area under the concentration-versus-time curve from zero to 12h (AUC)mediastinumfluid/serum and AUCpleuralfluid/serum ratio were 1.32 and 1.64, respectively. The results suggest that the linezolid concentration in the mediastinum varies as in the serum, and that the concentration in the mediastinum is the same as or greater than that in the serum.
    International journal of infectious diseases: IJID: official publication of the International Society for Infectious Diseases 05/2013; · 2.17 Impact Factor
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    ABSTRACT: Linezolid (LZD) is an option for treating infections caused by multi-resistant Gram-positive bacteria. The protein-binding rate of LZD markedly influences its elimination by dialysis, with limited data suggesting that LZD is cleared by intermittent hemodialysis. Here, we investigated the protein-binding rate and elimination efficiency of LZD in a sepsis patient receiving dialysis. The oral administration of LZD at 600 mg/day resulted in protein-binding and free rates of the drug of 20.4% and 79.6%, respectively, 24 h after administration. By comparing the LZD concentration before and after dialysis, the elimination efficiency of free LZD as a result of dialysis was found to be 40.6%. Our sepsis patient showed higher plasma concentrations of LZD at trough after hemodialysis than the reported concentrations in normal renal function patients. However, it is not clear from our present findings if a relationship exists between myelosuppression and plasma LZD concentration.
    Renal Failure 01/2013; · 0.94 Impact Factor
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    ABSTRACT: We investigated the pharmacokinetics of gentamicin in a haemodialysis patient treated for endocarditis caused by methicillin-resistant Staphylococcus aureus and found that the administration of gentamicin immediately prior to dialysis was a suitable strategy for reaching target maximum drug concentration (Cmax) values and low trough levels.
    Scandinavian Journal of Infectious Diseases 02/2012; 44(8):630-4. · 1.64 Impact Factor
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    ABSTRACT: We evaluated the pharmacokinetics of linezolid in the case of an obese Japanese patient (body weight 116 kg; body mass index 37 kg/m(2)). Linezolid was administered at a dose of 600 mg by intravenous drip infusion for 60-90 min at 12-h intervals. The results showed increased clearance of linezolid and a reduced serum concentration compared to population pharmacokinetic parameters, with trough levels below the 90% minimum inhibitory concentration. However, linezolid was effective for improving lung infection and inflammation in our patient, which may be due to its particularly effective transfer into lung tissues. Linezolid undergoes slow non-enzymatic oxidation in vivo that may be increased in obese patients, and this may account for the greater clearance. Our findings are useful for the planning of linezolid therapy in obese patients.
    Scandinavian Journal of Infectious Diseases 01/2012; 44(8):626-9. · 1.64 Impact Factor
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    ABSTRACT: We examined a method to determine the dose of carboplatin and the timing of hemodialysis in carboplatin-based chemotherapy for a hemodialysis patient with cancer. Carboplatin-based chemotherapy was performed for a patient with small-cell lung cancer who was receiving hemodialysis. The dose of carboplatin was calculated based on body surface area in the first cycle (480 mg/body, Day 1) and based on the Calvert formula with the aim of achieving AUC of 5 mg/ml min in the second cycle (170 mg/body, Day 1). Carboplatin was continuously infused for 1 h on Day 1 of each cycle. Hemodialysis was performed for 4 h beginning 1 h after administration of carboplatin. The AUC of free carboplatin administered in the first and second cycles was 13.45 and 5.74 mg/ml min, respectively, and t (1/2) was 24.66 and 21.84 h, respectively. Protein binding ratio depended on the time after administration and reached a value ≥50% only at ≥24 h administration. Based on the results of this study, a value close to the targeted AUC can be obtained in a hemodialysis patient with cancer when carboplatin is administered at a dose determined based on the Calvert formula. These results may be useful to achieve a targeted AUC in hemodialysis patients. A certain amount of carboplatin can be eliminated by performing hemodialysis in an early phase when protein binding ratio is low after transition to the elimination phase to enable stable the concentration.
    Cancer Chemotherapy and Pharmacology 12/2011; 69(3):845-8. · 2.80 Impact Factor
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    ABSTRACT: We evaluated the possible association between trough linezolid (LZD) concentrations and platelet counts using a dose-response curve with a logit model equation. We demonstrated that trough LZD concentrations correlated with platelet counts. A significant decrease in platelet count was observed in patients with trough LZD concentrations higher than 22.1 μg/ml.
    Scandinavian Journal of Infectious Diseases 09/2011; 44(1):60-4. · 1.64 Impact Factor
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    ABSTRACT: We describe a case of bacterial meningitis in a patient administered linezolid (LZD). The ratio of free to total LZD concentrations in cerebrospinal fluid (CSF) was 1 for all measurements, and the LZD concentration in CSF measured at the trough level was almost the same as the free serum concentration.
    Scandinavian Journal of Infectious Diseases 08/2011; 43(11-12):982-5. · 1.64 Impact Factor
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    ABSTRACT: Although linezolid (LZD) has proven effective for the treatment of infections caused by multidrug-resistant Gram-positive cocci, thrombocytopenia and anemia associated with reduced hemoglobin (Hb) levels are common side effects. To study the association between the development of these adverse effects and blood LZD levels, the authors evaluated the correlation between LZD clearance (LZD-CL), platelet (PLT) counts and Hb levels. Sixteen patients with methicillin-resistant Staphylococcus aureus infection were administered LZD over a period of 4 to 41 days, and blood was collected at variable time points beginning on day 4 (n = 31). Blood LZD levels were measured by high-performance liquid chromatography, and LZD-CL was estimated by the population pharmacokinetics mean parameter and Bayesian methods. The relationship between the estimated LZD-CL and reductions in PLT counts and Hb levels was then evaluated by regression analysis. During the LZD treatment period, a weak correlation was identified between the LZD-CL rate and PLT counts (r(2) = 0.31, n = 31). Significantly, the regression analysis between LZD-CL and Hb levels showed a stronger correlation (r(2) = 0.54, n = 31), with Hb levels clearly decreasing with reductions in the LZD-CL rate. In patients undergoing treatment with LZD, low LZD-CL rates correlated with reductions of both PLT counts and Hb levels, suggesting that increase of blood LZD levels influences hematopoietic function. Because a strong correlation was noted between LZD-CL and Hb levels, closely monitoring changes in Hb levels during treatment with LZD may detect the development of adverse effects such as thrombocytopenia and anemia.
    The American Journal of the Medical Sciences 06/2011; 342(6):456-60. · 1.52 Impact Factor
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    ABSTRACT: It has been proposed that it is not necessary to adjust the dose of linezolid (LZD) in patients with reduced renal function. However, significantly lower platelet counts and hemoglobin levels have been reported in such patients compared to those in patients with normal renal function. This suggests that the appropriate dose and administration method for LZD are yet to be established in patients with renal dysfunction. The subjects in this study were patients with renal dysfunction who developed adverse effects of thrombocytopenia and anemia during treatment with LZD. We investigated the association of these adverse effects with the blood LZD concentration and the area under the concentration-time curve from zero to 24 h (AUC(0-24)), determined using a one-compartment Bayesian model (n = 20). The measured blood LZD concentration was significantly higher than the predicted concentration in a population pharmacokinetics approach (p < 0.01), and severe thrombocytopenia developed as the blood LZD concentration increased. The platelet count and hemoglobin level decreased as the AUC(0-24) of LZD increased in patients with renal dysfunction, and the correlations were significant: r = 0.593 and r = 0.783, respectively (p < 0.01). These findings suggest that LZD administered to patients with renal dysfunction may reach a high blood level and subsequently increase the AUC(0-24), which may then induce adverse effects of severe thrombocytopenia and anemia.
    Journal of Infection and Chemotherapy 02/2011; 17(1):70-5. · 1.38 Impact Factor
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    ABSTRACT: Vancomycin (VCM) is a glycopeptide antibiotic that is generally used to treat methicillin-resistant Staphylococcus aureus (MRSA). Recently, it has been reported that VCM clearance (CL) is significantly higher in elderly patients and infants and children with malignancies, compared with those without malignancies. We have treated many patients with a variety of malignant tumors in whom serum VCM concentrations were found to be moderately lower during therapeutic drug monitoring (TDM). The aim of this study was to determine whether the presence of malignant tumors influences trough concentrations of VCM and VCM pharmacokinetics in elderly patients during treatment for MRSA infection. Comparison of the clinical characteristics and VCM pharmacokinetic parameters between patients with and without malignancies was undertaken in 49 elderly Japanese patients infected with MRSA. The mean trough concentration of VCM in patients with malignancies was significantly lower than that in patients without malignancies. Our results showed significantly higher values of VCM CL and volume of distribution and a shorter elimination half-life in patients with malignancies. Univariate logistic regression analysis of the pharmacokinetic parameters indicated that VCM CL contributed as a significant factor independent of the relation to malignant tumor. In conclusion, it is suggested that the therapeutic effects and side effects of VCM should be actively monitored using TDM, because concentrations may decrease when CL increases in VCM therapy for elderly patients with malignant tumors.
    Yakugaku zasshi journal of the Pharmaceutical Society of Japan 01/2010; 130(1):69-73. · 0.31 Impact Factor
  • Iryo Yakugaku (Japanese Journal of Pharmaceutical Health Care and Sciences). 01/2009; 35(8):525-533.
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    ABSTRACT: Linezolid (LZD) is thought not to require dose adjustment in patients with renal dysfunction, making it a drug of choice for these patients. However, in the current study we show LZD accumulation occurring with repeated dosing during hemodialysis in a 64-year-old man receiving hemodialysis treatment. In this patient, methicillin-resistant Staphylococcus aureus (MRSA) caused an abscess under the abdominal wall due to wound infection after colon cancer surgery. Treatment was initiated with intravenous LZD (600 mg) every 12 h. However, pancytopenia and liver dysfunction occurred during the LZD administration period. A high trough level, of 15-20 microg/ml, during LZD administration was determined from stored blood biochemistry samples, and pharmacokinetic parameters, estimated by the Bayesian nonlinear least squares method, were as follows: clearance (CL), 1.56 l/h; clearance during hemodialysis (CL(HD)), 2.23 l/h; volume of distribution (Vd), 18.69 l; and area under the curve (AUC), 384.07 microg/ml . h. Simulation of the serum concentration-time profile from the estimated pharmacokinetic parameters gave a trough level about four to five times higher than that in healthy individuals in the early administration period, indicating LZD accumulation in blood. These findings suggest a causal relationship between the high LZD level and the adverse effects. The cause of the high LZD level is unclear, but the findings indicate that careful monitoring and dose adjustment of LZD is necessary in hemodialysis patients.
    Journal of Infection and Chemotherapy 05/2008; 14(2):156-60. · 1.38 Impact Factor
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    ABSTRACT: Methotrexate (MTX) is the most important drug for treating rheumatoid arthritis (RA). It has been stated that cytokines play an important role in the pathogenesis of RA, and that cytokine levels increase and show 24-h rhythms in RA patients. Previously, we found that arthritis was relieved after the administration of MTX at specific times in synchronization with the 24-h rhythm of tumor necrosis factor (TNF)-α in collagen-induced arthritis (CIA) animals. Based on our findings in an earlier study of the dosing time-dependent effects of MTX in MRL/lpr mice, which develop autoimmune disorders that share similarities with human RA, we examined here the utility of MTX chronotherapy in Japanese RA patients. In an initial animal modeling study, we collected blood from MRL/lpr mice at different times (2, 6, 10, 14, 18, or 22 hours after the light was turned on [HALO]), and we measured TNF-α mRNA expression in leukocytes. MTX was administered to the mice at two different dosing times (6 or 18 HALO), and various blood parameters were measured to estimate arthritis activity. TNF-α mRNA levels showed a clear 24-h rhythm with a peak at 22 HALO and a trough at 18 HALO after RA had developed. In these MRL/lpr mice, inflammation and TNF-α were markedly reduced when the MTX dosing time was matched to the time (18 HALO) when the TNF-α level began to increase. We then applied these findings to Japanese RA patients by switching them from the standard MTX three times/wk (day 1: after breakfast and supper; day 2: after breakfast schedule), to chronotherapy, in which the dose and number of doses/wk were not changed but MTX was administered once-a-day at bedtime. Disease Activity Score (DAS)28, modified health assessment questionnaire (MHAQ), and adverse effects were assessed. With MTX chronotherapy, DAS28, which is commonly used to quantitatively assess RA symptoms, was significantly improved at all follow-up clinical visit times compared with the baseline (vs. 1 mo: p = .0197, 2 mos: p = .0107, 3 mos: p = .0087). Significant symptom recovery was observed in 41.2% of patients, and 23.5% of patients achieved clinical remission during the 3 mos of follow-up. Functional capacity of RA patients, as indicated by the MHAQ, was markedly improved by chronotherapy. There were no severe adverse effects. Thus, we demonstrated (i) inflammation and plasma TNF-α concentrations were significantly reduced in MRL/lpr mice treated with MTX at 18 HALO, the time when TNF-α mRNA level began to increase; and (ii) MTX bedtime chronotherapy was safe, markedly reduced disease activity, and improved the functional capacity of RA patients. The findings on RA patients show that bedtime MTX chronotherapy can improve RA symptoms compared to the current standard dosing methods.
    Chronobiology International 28(3):267-74. · 4.35 Impact Factor

Publication Stats

91 Citations
39.08 Total Impact Points


  • 2013
    • University of Toyama
      • Department of Hospital Pharmacy
      Тояма, Toyama, Japan
  • 2011–2013
    • National Hospital Organization Kumamoto Medical Center
      Kumamoto, Kumamoto Prefecture, Japan
  • 2010
    • NHO Nagasaki Medical Center
      Nagasaki, Nagasaki, Japan