Hidetoshi Kamimura

Correlation between serum linezolid concentration and the development of thrombocytopenia

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.

Pharmacokinetics of repeated dosing of linezolid in a hemodialysis patient with chronic renal failure.

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 μg/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 (CLHD), 2.23 l/h; volume of distribution (Vd), 18.69 l; and area under the curve (AUC), 384.07 μg/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.

Evaluation of the pharmacokinetics of linezolid in an obese Japanese patient

Abstract We evaluated the pharmacokinetics of linezolid in the case of an obese Japanese patient (body weight 116 kg; body mass index 37 kg/m2). 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.

Population Pharmacokinetic Analysis of Linezolid in Low Body Weight Patients with Renal Dysfunction

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 × eGFR0.428 × HB0.502 × 0.283 (ALT ≥ 100 IU/L) and CL (L/h) = 0.00327 × TBW × eGFR0.428 × HB0.502 (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.

Stimulating effect of activated charcoal beads on fecal excretion of 2,3,4,7,8-pentachlorodibenzofuran in rats

Abstract We investigated by using rats whether activated charcoal beads can stimulate the fecal excretion of and reduce the toxicity of 2,3,4,7,8-pentachloro-dibenzofuran (PenCDF), one of the most important causal agents of Yusho. The hypertrophy of liver and atrophy of thymus caused by an oral administration of PenCDF at a dose of 1 mg/kg were suppressed significantly by activated charcoal beads treatment for 3 weeks after a week interval from the day of PenCDF administration. Fecal excretion of PenCDF was stimulated approximately 3-fold, and the PenCDF level in the liver and blood tended to decline by this treatment.

Influence of Linezolid Clearance on the Induction of Thrombocytopenia and Reduction of Hemoglobin

Introduction: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. Methods: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. Results:During the LZD treatment period, a weak correlation was identified between the LZD-CL rate and PLT counts (r2 = 0.31, n = 31). Significantly, the regression analysis between LZD-CL and Hb levels showed a stronger correlation (r2 = 0.54, n = 31), with Hb levels clearly decreasing with reductions in the LZD-CL rate. Conclusions: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.

Successful treatment of skin and soft tissue infection due to carbapenem-resistant Acinetobacter baumannii by ampicillin–sulbactam and meropenem combination therapy

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 patients 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.

Enhanced faecal excretion of 2,3,4,7,8-pentachlorodibenzofuran in rats by a long-term treatment with activated charcoal beads.

1. The effect of activated charcoal beads on the faecal excretion of 2,3,4,7,8-pentachlorodibenzofuran (PenCDF), a causal agent of yusho, which accumulates in the body, was studied for 12 weeks in rats. 2. Diets supplemented with 1% and 5% activated charcoal beads stimulated faecal excretion of PenCDF about 2- and 4-fold, respectively. The concentration of PenCDF in liver, the major storage site, was decreased significantly and dose-dependently by the treatment. 3. The charcoal bead treatment decreased the extent of fatty liver, thymic atrophy, and induction of hepatic benzo[a]pyrene hydroxylase.

Mechanisms for stimulated fecal excretion of 2,3,4,7,8-pentachlorodibenzofuran in rats by treatment with squalane and liquid paraffin

Abstract Squalane and liquid paraffin stimulated the fecal excretion of 2,3,4,7,8-pentachlorodibenzofuran (PenCDF) about 3- and 2-fold, respectively, for 3 weeks in rats administered with 1 mg/kg of PenCDF. Squalane also enhanced the fecal excretion of PenCDF for 12 weeks in rats administered with 0.2 mg/kg of it. The accumulated PenCDF in rat body was considered to be mainly excreted through the intestinal wall into the lumen. The absorption of PenCDF was reduced by dissolving it in squalane or liquid paraffin. Thus these agents appear to stimulate the fecal excretion of PenCDF by the inhibition of the re-absorption of PenCDF which has been eliminated into the intestinal lumen.

Presence of both heterogeneous vancomycin-intermediate resistance and β-lactam antibiotic-induced vancomycin resistance phenotypes is associated with the outcome in methicillin-resistant Staphylococcus aureus bloodstream infection

Abstract Background: Although the individual expression of heterogeneous vancomycin-intermediate resistance (hVISA) and β-lactam antibiotic-induced vancomycin resistance (BIVR) phenotypes has been associated with treatment failure and recurrence in methicillin-resistant Staphylococcus aureus (MRSA) infections, the effect of the co-expression of these phenotypic profiles on clinical outcome has not been fully elucidated. The aim of this study was to determine the impact of the combination of hVISA and BIVR phenotypes on the clinical outcome in MRSA bacteremia. Methods: One hundred and sixty-two MRSA blood isolates from a 21-y period, 1987–2007, were randomly selected. Screening for hVISA was done by the macromethod Etest and confirmed by population analysis profiles. BIVR was identified using Mu3 agar containing 4 μg/ml of vancomycin. Results: Thirty (18.5%) and 39 (24.1%) of the 162 MRSA blood isolates were positive for the hVISA and BIVR phenotypes, respectively. Eighteen (11.1%) isolates possessed both hVISA and BIVR phenotypes (hVISA(+)/BIVR(+)). In a subset of patients who received initial treatment with glycopeptides, only the patients whose isolates were hVISA(+)/BIVR(+) displayed a significantly higher mortality rate in comparison to those with non-hVISA(+)/BIVR(+) (80.0% vs 31.3%, p = 0.004). The presence of both hVISA and BIVR phenotypes was a predictor of mortality using a logistic regression analysis (p = 0.025). Conclusions: The combined phenotype of hVISA and BIVR was associated with a higher probability of mortality in patients with MRSA bacteremia. Further prospective studies are warranted to delineate the clinical significance of the combined phenotype of hVISA and BIVR.