[Show abstract][Hide abstract] 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. · 2.84 Impact Factor
[Show abstract][Hide abstract] 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
[Show abstract][Hide abstract] 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
[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] ABSTRACT: Acinetobacter baumannii has emerged worldwide as an important nosocomial pathogen in medical institutions. Here, we present the draft genome sequences of A. baumannii strains MRY09-0642, MRY10-0558, and MRY12-0277 that were isolated from nosocomial outbreaks in Japan between 2008 and 2012 and that are resistant to antimicrobial agents, including carbapenems, fluoroquinolones, and aminoglycosides.
[Show abstract][Hide abstract] ABSTRACT: Pseudomonas alcaligenes, a Gram-negative aerobic bacterium, is a rare opportunistic human pathogen. Here, we report the whole-genome sequence of P. alcaligenes strain MRY13-0052, which was isolated from a bloodstream infection in a medical institution in Japan and is resistant to antimicrobial agents, including broad-spectrum cephalosporins and monobactams.
[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] 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
[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] ABSTRACT: Factors related to poor outcome in drug-resistant bacterial infection treatment were analyzed based on surveys at 54 National Hospital Organization facilities. Results showed common etiological causes of Methicillin-resistant Staphylococcus aureus (MRSA) and Penicillin-resistant Streptococcus pneumoniae (PRSP). Specifically, the odds ratio in the elderly, aged 75 years and older, was 1.473 (p=0.006) for MRSA and 6.401 (p=0.0001) for PRSP. Among those undergoing tracheal intubation, the odds ratio was 1.767 (p=0.021) for MRSA and 4.185 (p=0.0001) for PRSP, showing that advanced age and tracheal intubation tended to aggravate disease. MRSA-specific causes were pneumonia with an odds ratio of 2.426 (p=0.0001) and sepsis with one of 1.417 (p=0.013). Causes specific to Multi-drug resistant Pseudomonas aeruginosa (MDRP) were Intravenous hyperalimentation (IVH) with an odds ratio of 2.078 (p=0.0001) and urinary-tract infection with one of 0.566 (p=0.027). The individual roles of these factors in poor outcomes must thus be clarified to develop preventive measures against them.
Kansenshogaku zasshi. The Journal of the Japanese Association for Infectious Diseases 09/2011; 85(5):488-93.
[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] 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. · 1.33 Impact Factor
[Show abstract][Hide abstract] 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. · 1.55 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: There have been many studies of therapeutic drug monitoring (TDM) of vancomycin (VCM) based on Bayesian analysis, but there have been no reports of the accuracy of prediction based on Bayesian-estimated patient-specific parameters. This study was conducted to compare the accuracy of prediction based on the population pharmacokinetic (PPK) method and Bayesian-estimated parameters.
The subjects were 22 patients who were treated with VCM for MRSA infection and whose blood was sampled twice or more during the administration period. The concentrations between the blood samples were predicted based on the concentrations in the first blood samples based on the PPK method using mean parameters for the Japanese population and Bayesian-estimated patient-specific pharmacokinetic parameters. The mean prediction error (ME), mean absolute error (MAE) and root mean squared error (RMSE) were compared to examine the accuracy of prediction based on Bayesian-estimated patient-specific parameters.
The mean measured VCM concentration was 10·43±5·19 μg/mL, whereas the mean concentration predicted based on the PPK method was 8·52±4·34 μg/mL, with an ME of -1·91, MAE of 2·93 and RMSE of 3·21. The mean concentration predicted based on patient-specific parameters was 9·62±4·95 μg/mL with ME of -0·81, MAE of 1·38 and RMSE of 1·74. The ME and MAE for the concentrations predicted using patient-specific parameters were smaller compared with those predicted using the PPK method (P=0·0471 and 0·0003, respectively), indicating superior prediction with a significant difference between approaches.
Prediction using Bayesian estimates of patient-specific parameters was better than by the PPK method. However, when using patient-specific parameters it is still necessary to fully understand the clinical status of the patient and frequently determine VCM concentrations.
Journal of Clinical Pharmacy and Therapeutics 10/2010; 35(5):527-32. · 2.10 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Renal function was estimated in 129 elderly patients with methicillin-resistant Staphylococcus aureus (MRSA) who were treated with vancomycin (VCM). The estimation was performed by substituting serum creatinine (SCR) measured enzymatically and a value converted using the Jaffe method into the Cockcroft-Gault and Modification of Diet in Renal Disease (MDRD) equations. The serum trough level was predicted from three estimates of renal function by the population mean (PM) and Bayesian methods and the predictability was assessed.
Two-compartment model-based Japanese population parameters for VCM were used, and the mean prediction error (ME) and root mean squared error (RMSE) were calculated as indices of bias and accuracy, respectively, for predictions by the PM and Bayesian methods.
The PM method gave the highest correlation with the measured value using the estimate of renal function obtained by substituting the Jaffe-converted SCR into the Cockcroft-Gault equation. There was no positive or negative bias in the ME and the value was significantly smaller than for other predicted data (P < 0.05). RMSE was also the smallest, indicating that this method increases the predictability of the serum VCM trough level. While, ME showed a negative bias for all values predicted by the Bayesian method, both the ME and RMSE were very small.
In the application of the PM method for VCM treatment of elderly patients with MRSA, substitution of SCR based on the Jaffe method into the Cockcroft-Gault equation increases the predictability of the serum VCM trough level. The Bayesian method predicted the serum VCM trough level with high accuracy using any of the estimates of renal function.
Journal of Clinical Pharmacy and Therapeutics 09/2009; 34(4):465-72. · 2.10 Impact Factor
[Show abstract][Hide abstract] 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. · 1.55 Impact Factor