Pharmacokinetics of cefmetazole in plasma, peritoneal fluid, peritoneum, and subcutaneous adipose tissue of patients scheduled for lower gastrointestinal surgery: Dosing considerations based on site-specific pharmacodynamic target attainment.

INTRODUCTION: Cefmetazole (CMZ) has gained interest as a carbapenem-sparing alternative to the epidemic of extended-spectrum ß-lactamase (ESBL)-producing Enterobacterales (ESBL-E). In this study, we investigated the pharmacokinetics (PK) of CMZ in plasma, peritoneal fluid, peritoneum, and subcutaneous adipose tissue to assess the dosing regimen needed to achieve pharmacodynamic (PD) goals at the target site. METHODS: Patients scheduled for elective lower gastrointestinal surgery were intravenously administered CMZ. Plasma, peritoneal fluid, peritoneum, and subcutaneous adipose tissue samples were collected after CMZ infusion and during the surgery, and CMZ concentrations were measured. The non-compartmental and compartmental PK parameters were estimated and used to evaluate site-specific PD target attainment. RESULTS: A total of 38 plasma, 27 peritoneal fluid, 36 peritoneum, and 38 subcutaneous adipose tissue samples were collected from 10 patients. The non-compartmental PK analysis revealed the ratios of the mean area under the drug concentration-time curve (AUC0-3.5 h) of peritoneal fluid-to-plasma, peritoneum-to-plasma, and subcutaneous adipose tissue-to-plasma were 0.60, 0.36, and 0.11, respectively. The site-specific PD target attainment analyses based on the breakpoints for ESBL-E per the Japanese surgical site infection (SSI) surveillance (MIC90 = 8 mg/L) revealed that 2 g CMZ every 3.5 h achieved desired bactericidal effect at all sites and 2 g CMZ every 6 h achieved PD goals at peritoneum and peritoneal fluid. CONCLUSION: These findings clarify the PK of CMZ in abdominal tissues and could help decide optimal dosing regimens to treat intra-abdominal infection and prophylaxis of SSI.

Pharmacokinetics of flomoxef in plasma, peritoneal fluid, peritoneum, and subcutaneous adipose tissue of patients undergoing lower gastrointestinal surgery: Dosing considerations based on site-specific pharmacodynamic target attainment.

INTRODUCTION: Flomoxef is generally used to treat abdominal infections and as antibiotic prophylaxis during lower gastrointestinal surgery. It is reportedly effective against extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae and an increasingly valuable alternative to carbapenems. However, its abdominal pharmacokinetics remain unclear. Herein, pharmacokinetic analysis of flomoxef in the abdominal tissue was conducted to simulate dosing regimens for pharmacodynamic target attainment in abdominal sites. METHODS: Flomoxef (1 g) was administered intravenously to a patient 30 min before commencing elective lower gastrointestinal surgery. Samples of plasma, peritoneal fluid, peritoneum, and subcutaneous adipose tissue were collected during surgery. The flomoxef tissue concentrations were measured. Accordingly, non-compartmental and compartmental pharmacokinetic parameters were calculated, and simulations were conducted to evaluate site-specific pharmacodynamic target values. RESULTS: Overall, 41 plasma samples, 34 peritoneal fluid samples, 38 peritoneum samples, and 41 subcutaneous adipose samples from 10 patients were collected. The mean peritoneal fluid-to-plasma ratio in the areas under the drug concentration-time curve was 0.68, the mean peritoneum-to-plasma ratio was 0.40, and the mean subcutaneous adipose tissue-to-plasma was 0.16. The simulation based on these results showed the dosing regimens (q8h [3 g/day] and q6h [4 g/day]) achieved the bactericidal effect (% T > minimum inhibitory concentration [MIC] = 40%) in all tissues at an MIC of 1 mg/L. CONCLUSIONS: We elucidated the pharmacokinetics of flomoxef and simulated pharmacodynamics target attainment in the abdominal tissue. This study provides evidence concerning the use of optimal dosing regimens for treating abdominal infection caused by strains like ESBL-producing bacteria.

Pharmacokinetic and pharmacodynamic simulation for the quantitative risk assessment of linezolid-associated thrombocytopenia.

WHAT IS KNOWN AND OBJECTIVE: Linezolid (LZD) may cause thrombocytopenia, which can result in discontinuation of treatment. In this study, the blood LZD trough concentration was estimated based on population pharmacokinetic (PK) parameters derived from two previously published models in the Japanese population to determine the rate of achieving the target trough value when the risk of thrombocytopenia is low and to clarify its relationship with the onset of thrombocytopenia. METHODS: This study included adult patients hospitalized at Shimane University Hospital, who received LZD treatment for at least 4 days from January 2010 to December 2017. Patients whose platelet count fell below 70% before LZD administration were categorized as the thrombocytopenic group. Patient PK parameters were calculated based on the population PK models described by Matsumoto et al. and Sasaki et al., and these parameters were designated A and B, respectively. Based on these parameters, the rate of achieving an LZD trough concentration of less than 8 µg/ml, which is the safety target achievement rate, was calculated using a random simulation for each patient. We further analysed the association between the incidence of thrombocytopenia and patient factors, including safety target achievement rate, through univariate, multivariate, and receiver operating characteristic (ROC) analyses. RESULTS AND DISCUSSION: Patients (n = 77) aged 72 ± 11 years and weighing 56.7 ± 10.9 kg, with a creatinine clearance (CLcr ) of 60.5 ± 47.2 ml/min and a cirrhosis prevalence of 9.1%, were analysed. All patients received LZD at a dose of 600 mg twice daily for a total of 10.9 ± 8.9 days. Univariate analyses revealed significant differences (p < 0.05) in the duration of LZD therapy, serum creatinine, creatinine clearance, LZD clearance, and the safety target achievement rate for parameters A and B between the thrombocytopenic and non-thrombocytopenic groups. A multivariate analysis of these factors stratified with the cutoff values obtained by ROC analysis revealed that the duration of LZD therapy and the safety target achievement rates for parameters A and B were significant factors (odds ratios for duration of LZD therapy: 7.436 [95% confidence interval (CI): 1.918-28.831] and 4.712 [95% CI: 1.567-14.163]; odds ratio for safety target achievement rate: 0.060 [95% CI: 0.016-0.232] and 0.167 [95% CI: 0.056-0.498] for parameters A and B, respectively). When the safety target achievement rates for patients treated with LZD were compared between the thrombocytopenic and non-thrombocytopenic groups, the safety target achievement rate was higher in the non-thrombocytopenic group in both the patients treated with LZD for less than 10 days and those for 10 days or more. Therefore, the safety target achievement rate estimated by the PK/PD simulation may represent to be an important index for risk assessment of LZD-induced thrombocytopenia. WHAT IS NEW AND CONCLUSION: The risk of LZD-induced thrombocytopenia, which increased with the duration of LZD therapy, may be predicted using the safety target achievement rate obtained by the blood concentration simulation.

Population Pharmacokinetics of Teicoplanin and Its Dosing Recommendations for Neutropenic Patients With Augmented Renal Clearance for Hematological Malignancies.

BACKGROUND: Plasma teicoplanin concentrations do not reach the therapeutic range in several patients with hematological malignancies. Nevertheless, the characteristics of the population pharmacokinetic (PPK) models have not been clarified for malignancy. The decrease in the teicoplanin concentration in patients with cancer has been attributed to augmented renal clearance (ARC). It is essential to identify the causative factors of ARC to construct a PPK model to optimize the administration method. The authors aimed to establish a PPK model and develop an appropriate dosing regimen for teicoplanin in patients with hematological malignancies. METHODS: PPK analysis was performed using therapeutic drug monitoring (TDM) data from 119 patients with hematological malignancies. The developed model was verified by predictive performance. RESULTS: The covariates affecting systemic clearance were serum creatinine, presence or absence of neutropenia (<500/µL), and body size descriptor. Patients with hematologic malignancies and neutropenia showed a 25% increase in clearance compared with those with a normal neutrophil count. The PPK model was constructed based on the presence or absence of neutropenia. This model allowed the selection of the most appropriate dosage regimen out of those recommended by the TDM guidelines for patients with eGFR of >60 mL/min/1.73 m2. The PPK model predicted a dosing regimen for achieving a 10% improvement in the coverage probability of the target concentration range during the loading and maintenance phases. CONCLUSIONS: The PPK model may help optimize dose regimens and evaluate dosing methods, using comparative simulations, in patients with hematological malignancies.

Dosing Optimization of Ampicillin-Sulbactam Based on Cystatin C in Elderly Patients with Pneumonia.

Ampicillin-sulbactam is a first-line therapy for pneumonia and is mainly excreted by the kidney. It is important to optimize the dose and dosing interval of ampicillin-sulbactam because in patients with decreased renal function and low skeletal muscle mass, such as the elderly, excess drug may burden renal function. In this study, we evaluated indices of renal function and optimized the dose and dosing interval of ampicillin-sulbactam based on pharmacokinetics (PK) and pharmacodynamics theory in elderly patients. The serum concentrations of ampicillin and sulbactam were measured by HPLC, and PK parameters were calculated. Correlations between the clearance of ampicillin or sulbactam and renal function were evaluated, and dosing optimization was calculated based on PK parameters. The PK parameters of ampicillin were CL = 6.5 ± 4.0 L/h, Vd = 19.3 ± 0.2 L, Ke = 0.4 ± 0.2, and t1/2 = 2.7 ± 1.6 h. The most correlated renal function index was estimated glomerular filtration rate (eGFRcys-c) calculated by serum cystatin-c (r = 0.7374, correlation formula; CL of ampicillin = 0.1937 × eGFRcys-c-0.6726). Based on this formula, we calculated the clearance of ampicillin and developed dosing regimens for the elderly. Serum cystatin-c concentration is an ideal index to optimize ampicillin-sulbactam antimicrobial therapy in elderly patients with pneumonia.

Clinical pharmacokinetics of flomoxef in prostate tissue and dosing considerations for prostatitis based on site-specific pharmacodynamic target attainment.

Flomoxef is used to treat bacterial prostatitis; however, its prostatic pharmacokinetics have not been fully clarified. Flomoxef (500 or 1000 mg) was administered to patients with benign prostatic hypertrophy (n = 54). After a 0.5-h infusion, venous blood samples were drawn at time points of 0.5-5 h, and prostate tissue samples were collected at time points of 0.5-1.5 h during transurethral resection of the prostate. The drug concentrations in plasma and prostate tissue were analyzed pharmacokinetically and used for a stochastic simulation to predict the probability of attaining pharmacodynamic target in prostate tissue. Showing dose linearity in the prostatic pharmacokinetics, flomoxef rapidly penetrated into prostate tissue, with a prostate/plasma ratio of 0.48-0.50 (maximum drug concentration) and 0.42-0.55 (area under the drug concentration-time curve). Against the tested populations of Escherichia coli, Klebsiella and Proteus species isolates, 0.5-h infusion of 1000 mg three times daily achieved a ≥90% expected probability of attaining the bactericidal target (70% of the time above the minimum inhibitory concentration [MIC]) in prostate tissue. The site-specific pharmacodynamic-based breakpoint (the highest MIC at which the target-attainment probability in prostate tissue was >90%) values were 0.25 mg/L (MIC for 90th percentile of E. coli and Klebsiella species) for 500 mg four times daily and 0.5 mg/L (MIC90 of Proteus species) for 1000 mg four times daily. These results help to fully characterize the prostatic pharmacokinetics of flomoxef, while also helping to rationalize and optimize the dosing regimens for prostatitis based on site-specific pharmacodynamic target attainment.

Clinical pharmacokinetics of oral azithromycin in epididymal tissue.

OBJECTIVES: Chlamydia trachomatis is one of the major pathogens causing acute epididymitis. Azithromycin (AZM) has a good efficacy against C. trachomatis; however, the ability of AZM to penetrate into human epididymal tissue has not yet been fully elucidated. Here, we examined the appropriate dosage of oral AZM for human epididymal tissue by site-specific pharmacokinetic/pharmacodynamic (PK/PD) analysis. METHODS: Patients with prostate cancer who underwent orchiectomy were included in this study. All patients received a 1-g dose of AZM before orchiectomy. Both epididymal tissue and blood samples were collected during surgery, and the drug concentrations were measured by high-performance liquid chromatography. All concentration-time data were analyzed with a three-compartment model with first-order absorption and elimination processes to simulate AZM concentrations in serum and epididymal tissue. RESULTS: A total of 10 patients were enrolled in the current study. For the observed values, the ratio of the epididymal concentration to the serum concentration was 5.13 ± 3.71 (mean ± standard deviation). For the simulated values, the maximum concentrations were 0.64 µg/mL at 2.42 h in serum and 1.96 µg/g at 4.10 h in epididymal tissue. The 24-h concentrations were 0.239 µg/mL in serum and 0.795 µg/g in epididymal tissue. CONCLUSIONS: The penetration of oral AZM into human epididymal tissue was examined to assess the potential application of AZM for the treatment of acute epididymitis. Based on the previous reports mentioning drug-susceptibility of C. trachomatis, multiple doses of oral AZM 1 g would be recommended for epididymitis based on the site-specific PK/PD.

Influence of GST polymorphisms on busulfan pharmacokinetics in Japanese children.

BACKGROUND: Fatal adverse effects or relapse can occur with excessive or insufficient busulfan exposure in hematopoietic stem cell transplantation. Given that busulfan is mainly metabolized by glutathione S-transferase (GST), we investigated the influence of GST polymorphisms on busulfan pharmacokinetics in Japanese pediatric patients. METHODS: Blood samples were taken from patients receiving high-dose i.v. busulfan as the first dose. Plasma busulfan concentration was measured using high-performance liquid chromatography. The area under the plasma busulfan concentration-time curve (AUC) was calculated. The genotype of GSTA1 was determined on polymerase chain reaction (PCR)-restriction fragment length polymorphism. Multiplex PCR was used to detect the presence or absence of GSTM1 and GSTT1 in the genomic DNA samples. RESULTS: Twenty patients were consecutively enrolled. Phenotype prediction was defined as follows: poor metabolizer (n = 4), one or more GSTA1*B haplotype or GSTM1/GSTT1 double-null genotypes; and extensive metabolizer (n = 16), other genotypes. GSTA1, M1, and T1 independently had no significant differences in AUC0-∞ , clearance or elimination rate constant. For the infant with unexpectedly high AUC0-∞ (2,591 µmol/L min), the GSTA1, M1, and T1 polymorphisms were wild type. On further analysis, the poor metabolizer group had lower clearance and higher AUC0-∞, except for the aforementioned patient, compared with the extensive metabolizer group (1,531 vs 1,010 µmol/L min; P < 0.01). CONCLUSIONS: GST polymorphisms may have affected busulfan pharmacokinetics, but these effects were obscured by other factors, such as underlying disease, systemic conditions, treatment history, and race.

Clinical pharmacokinetics and pharmacodynamic target attainment of pazufloxacin in prostate tissue: Dosing considerations for prostatitis.

The present study examined the clinical pharmacokinetics of pazufloxacin in prostate tissue and estimated the probability of target attainment for tissue-specific pharmacodynamic goals related to treating prostatitis using various intravenous dosing regimens. Patients with prostatic hypertrophy received prophylactic infusions of pazufloxacin (500 mg, n = 23; 1000 mg, n = 25) for 0.5 h prior to transurethral prostate resection. Drug concentrations in plasma (0.5-5 h) and prostate tissue (0.5-1.5 h) were measured by high-performance liquid chromatography and used for subsequent noncompartmental and three-compartmental analysis. Monte Carlo simulation was performed to evaluate the probability of target attainment of a specific minimum inhibitory concentration (MIC) in prostate tissue: the proportion that achieved both area under the drug concentration over time curve (AUC)/MIC = 100 and maximum concentration (Cmax)/MIC = 8. Prostatic penetration of pazufloxacin was good with mean Cmax ratios (prostate tissue/plasma) of 0.82-0.99 and for AUC, 0.80-0.98. The probability of reaching target MIC concentrations in prostate tissue was more than 90% for dosing schedules of 0.25 mg/L for 500 mg every 24 h (500 mg daily), 0.5 mg/L for 500 mg every 12 h (1000 mg daily), 1 mg/L for 1000 mg every 24 h (1000 mg daily), and 2 mg/L for 1000 mg every 12 h (2000 mg daily). Importantly, the 2000 mg daily regimen of pazufloxacin produced a profile sufficient to have an antibacterial effect in prostate tissue against clinical isolates of Escherichia coli and Klebsiella pneumonia with MIC values less than 2 mg/L.

Clinical pharmacokinetics of oral levofloxacin and sitafloxacin in epididymal tissue.

OBJECTIVES: This study aimed to investigate the penetration of fluoroquinolones into human epididymal tissue. METHODS: The penetration of levofloxacin (LVFX) 500 mg or sitafloxacin (STFX) 100 mg into epididymal tissue was examined. Patients with prostate cancer who were referred for orchiectomy were included. LVFX 500 mg (n = 9) or STFX 100 mg (n = 9) was administered orally 1 h before orchiectomy, and 0.5 g of epididymal tissue and blood samples were collected simultaneously during surgery. Drug concentrations were measured by high-performance liquid chromatography, and patient characteristics and adverse events were analyzed. RESULTS: The mean ratio of the epididymal concentration to the serum concentration was 1.48 ± 0.45 for LVFX and 1.54 ± 0.81 for STFX. For LVFX, the simulated curves estimated the following: maximum concentrations (Cmax) of 8.84 µg/ml in serum and 14.1 µg/g in epididymal tissue and area under the concentration-time curve for 24 h (AUC24) of 68.5 µg h/ml in serum and 108.9 µg h/g in epididymal tissue. For STFX, the Cmax was 1.22 µg/ml in serum and 1.66 µg/g in epididymal tissue, and the AUC24 was 9.58 µg h/ml in serum and 13.1 µg h/g in epididymal tissue. Neither treatment-related adverse events nor postoperative urogenital infections were observed. CONCLUSIONS: The results of this study suggest that oral administration of LVFX 500 mg or STFX 100 mg achieves effective epididymal concentrations for treatment of epididymitis.

Pharmacokinetics of Prophylactic Ampicillin-Sulbactam and Dosing Optimization in Patients Undergoing Cardiovascular Surgery with Cardiopulmonary Bypass.

UNLABELLED: Antibiotic concentrations must be maintained at an adequate level throughout cardiovascular surgery to prevent surgical site infection. This study aimed to determine the most appropriate timing for intraoperative repeated dosing of ampicillin-sulbactam, a commonly used antibiotic prophylaxis regimen, to maintain adequate concentrations throughout the course of cardiovascular surgery with cardiopulmonary bypass (CPB). The total plasma concentrations of ampicillin were monitored in 8 patients after ampicillin (1 g)-sulbactam (0.5 g) administration via initial intravenous infusion and subsequent CPB priming. Pharmacokinetic parameters were estimated and used to predict the free plasma concentrations of ampicillin. The mean values for the volume of distribution, elimination rate constant, elimination half-life, and total clearance of ampicillin were 15.8±4.1 L, 0.505±0.186 h(-1), 1.52±0.47 h, and 7.72±2.72 L/h, respectively. When ampicillin (1 g)-sulbactam (0.5 g) was intravenously administered every 3, 4, 6, and 12 h after the start of CPB, the predicted free trough plasma concentrations of ampicillin were 15.20, 8.25, 2.74, and 0.13 µg/mL, respectively. Therefore, an every-6-h regimen was needed to maintain the free ampicillin concentration at more than 2 µg/mL during cardiovascular surgery with CPB. We suggest that the dose and dosing interval for ampicillin-sulbactam should be adjusted to optimize the efficacy and safety of treatment, according to the minimum inhibitory concentrations for methicillin-sensitive Staphylococcus aureus isolates at each institution. REGISTRATION NUMBER: UMIN000007356.

Risk factors for ganciclovir-induced thrombocytopenia and leukopenia.

Ganciclovir is a nucleoside guanosine analogue that exhibits therapeutic activity against human cytomegalovirus infection, and is primarily excreted via glomerular filtration and active tubular secretion. The adverse effects induced by ganciclovir therapy are generally of a hematological nature and include thrombocytopenia and leukopenia. Low marrow cellularity and elevated serum creatinine have been identified as risk factors for ganciclovir-induced neutropenia. However, the risk factors for thrombocytopenia have yet to be determined. Therefore, this study investigated patients administered ganciclovir to determine the risk factors for thrombocytopenia and leukopenia. Thrombocytopenia occurred in 41 of these patients (30.6%). Multivariate logistic regression analysis identified three independent risk factors for thrombocytopenia: cancer chemotherapy (odds ratio (OR)=3.1), creatinine clearance (<20 mL/min) (OR=12.8), and the ganciclovir dose (≥12 mg/kg/d) (OR=15.1). Leukopenia occurred in 36 patients (28.6%), and white blood cell count (<6000 cells/mm(3)) (OR=3.7) and the ganciclovir dose (≥12 mg/kg/d) (OR=7.8) were identified as risk factors. These results demonstrated that several factors influenced the occurrence of ganciclovir-induced thrombocytopenia and leukopenia, and suggest that special attention should be paid to patients receiving cancer chemotherapy with a low creatinine clearance (<20 mL/min) and high dose (≥12 mg/kg/d) in order to avoid ganciclovir-induced thrombocytopenia.

Evaluation of a pharmacokineticpharmacodynamic approach using software to optimize the carbapenem antibiotic regimen.

OBJECTIVE: Meropenem (MEPM) and doripenem (DRPM), whose antipseudomonal activity is more potent than that of other carbapenem antimicrobials, were used in the study. Monte Carlo simulation of drug concentrations was performed to develop an administration plan for MEPM and DRPM that takes into account the pharmacokinetics (PK)-pharmacodynamics (PD) of MEPM and DRPM and the renal function of each patient. Drug administration plans were proactively applied to patients with pneumonia to determine the usefulness of the method by assessing treatment efficacy and safety. METHODS: Patients with healthcareassociated pneumonia and an indication for MEPM or DRPM chemotherapy underwent drug administration in accordance with the MEPM and DRPM treatment plan developed by the PK-PD software applications. The primary efficacy endpoints were the clinical and bacteriological efficacy of the drugs agains pneumonia. The safety of the antimicrobials was assessed based on abnormal laboratory findings and the seizure disorders in accordance with the criteria for safety evaluation of antimicrobial agents. RESULTS: This study examined 12 and 11 patients in the MEPM and DRPM group, respectively; however, 3 DRPM patients were excluded due to the administration of anti-methicillin-resistant Staphylococcus aureus drugs after the initiation of DRPM treatment. MEPM and DRPM drug administration was determined to be safe and effective in all patients. CONCLUSIONS: The present results suggest that the Monte Carlo simulation-based PK-PD software is an effective tool for planning individualized antimicrobial chemotherapy with carbapenem in accordance with the PK-PD theory of antimicrobials. It is also possible to propose safe and effective drug administration plans for patients with healthcare-associated pneumonia.

Population pharmacokinetic-pharmacodynamic target attainment analysis of sulbactam in patients with impaired renal function: dosing considerations for Acinetobacter baumannii infections.

UNLABELLED: This study aimed to perform a pharmacokinetic (PK)-pharmacodynamic (PD) target attainment analysis of sulbactam against Acinetobacter baumannii in patients with impaired renal function. The PK data (188 plasma samples and 27 urine samples) were modeled simultaneously. The mean population parameters were CLr (l/h) = 0.0792 × CLcr (ml/min), CLnr (l/h) = 2.35, Vc (l) = 12.2, Q (l/h) = 4.68 and Vp (l) = 4.44, where CLr and CLnr are the renal and non-renal clearances, Vc and Vp are the distribution volumes of the central and peripheral compartments and Q is intercompartmental clearance. The creatinine clearance (CLcr) was the most significant covariate. The determined MIC of sulbactam against A. baumannii clinical isolates (n = 27) was 0.75-6.0 µg/ml with MIC50 and MIC90 of 1 and 4 µg/ml, respectively. For sulbactam regimens, a Monte Carlo simulation estimated the probabilities of attaining the bactericidal target (60% of the time above the MIC) and determined the PK-PD breakpoints (the highest MICs at which the probabilities were 90% or more). In a patient with a CLcr of 15 ml/min, a regimen of 1 g twice daily achieved a 90% or more probability against the A. baumannii isolate population; however, 2 g four times daily was needed for a 90% or more probability in a patient with a CLcr of 90 ml/min. The results of the PK-PD target attainment analysis are useful when choosing the sulbactam regimen based on the CLcr of the patient and the susceptibility of A. baumannii. REGISTRATION NUMBER: UMIN000007356.

Pharmacokinetics and dosing estimation of meropenem in Japanese patients receiving continuous venovenous hemodialysis.

The pharmacokinetics of meropenem have not yet been examined in Japanese patients receiving Continuous venovenous hemodialysis (CVVHD). The aim of this clinical investigation was to determine the pharmacokinetic parameters of meropenem in critically ill patients receiving CVVHD in order to estimate dosing regimens for the patient population in Japan. The values of pharmacokinetic parameters were 17.5 ± 5.6 l for V1, 1.27 ± 0.38 h(-1) for K12, 0.71 ± 0.40 h(-1) for K21 and 0.17 ± 0.02 h(-1) for K10. Based on these mean parameters (V1, K12, K21 and K10), time above MIC (T > MIC) values were estimated at different MICs using various meropenem regimens. For bacteria with a meropenem MIC of ≤ 2 µg/ml, a dosing regimen of 0.25 g every 24 h achieved more than 40% T > MIC. For a MIC of 4 µg/ml, all the regimens tested, except for 0.25 g every 24 h, achieved more than 40% T > MIC. For a MIC of 16 µg/ml, dosing regimens of 0.5 g every 8 h, 1 g every 12 h, and 1 g every 8 h achieved 40% T > MIC, reaching the pharmacokinetic-pharmacodynamic target range. This is the first study to examine the pharmacokinetics of meropenem under a CVVHD setting in Japan. The pharmacokinetic-pharmacodynamic profile of dosing regimens tested in this study will assist in selecting the appropriate meropenem regimens for patients receiving CVVHD.

Linezolid dosage in pediatric patients based on pharmacokinetics and pharmacodynamics.

Linezolid pharmacokinetic profile in pediatric patients has not been fully characterized, and the dose needed to achieve a pharmacokinetic-pharmacodynamic (PK-PD) target has yet to be established because its efficacy is associated with the area under the plasma drug concentration-time curve (AUC24)/minimum inhibitory concentration (MIC) ratio. The present study aimed to define the pharmacokinetic parameters of intravenous linezolid in pediatric patients and assess the rationale for the approved dosage recommendations. Linezolid was safe, tolerated well, and clinically effective for treating Gram-positive bacteria in five pediatric patients (3-11 years). The mean values for the volume of distribution and total clearance (CL) in a one-compartment model were estimated to be 0.646 ± 0.239 l/kg and 0.171 ± 0.068 l/h/kg, respectively (mean ± S.D.). Based on this analysis, the AUC24 and trough drug concentration in plasma (C(min)) for linezolid doses were predicted to be 175.4 µg h/ml and 3.4 µg/ml for 30 mg/kg/day, 204.7 µg h/ml and 4.3 µg/ml for 35 mg/kg/day, and 263.2 µg h/ml and 6.2 µg/ml for 45 mg/kg/day, respectively. Taking into account that AUC24 should be ≥ 200 µg h/ml for MIC of 2.0 µg/ml (to achieve an AUC24/MIC ratio of ≥ 100) and C(min) should be approximately 7 µg/ml (to avoid thrombocytopenia), we consider the approved dosage of 30 mg/kg/day to be fundamentally rational, but can be underdosed against bacteria with MIC of 2.0 µg/ml; therefore, a dose of 35-45 mg/kg/day is more appropriate to ensure the efficacy and safety of linezolid in pediatric patients.

Penetration of piperacillin-tazobactam into human prostate tissue and dosing considerations for prostatitis based on site-specific pharmacokinetics and pharmacodynamics.

This study aimed to investigate the penetration of PIPC-TAZ into human prostate, and to assess effectiveness of PIPC-TAZ against prostatitis by evaluating site-specific PK-PD. Patients with prostatic hypertrophy (n = 47) prophylactically received a 0.5 h infusion of PIPC-TAZ (8:1.2-0.25 g or 4-0.5 g) before transurethral resection of the prostate. PIPC-TAZ concentrations in plasma (0.5-5 h) and prostate tissue (0.5-1.5 h) were analyzed with a three-compartment PK model. The estimated model parameters were, then used to estimate the drug exposure time above the minimum inhibitory concentration for bacteria (T > MIC, the PD indicator for antibacterial effects) in prostate tissue for six PIPC-TAZ regimens (2.25 or 4.5 g; once, twice, three times or four times daily; 0.5 h infusions). Prostate tissue/plasma ratio of PIPC was about 36% both for the maximum drug concentration (Cmax) and the area under the drug concentration-time curve (AUC). Against MIC distributions for isolates of Escherichia coli, Klebsiella species and Proteus species, regimens of 4.5 g twice daily and 2.25 g three times daily achieved a >90% probability of attaining the bacteriostatic target for PIPC (30% T > MIC) in prostate tissue; regimens of 4.5 g three times daily and 2.25 g four times daily achieved a >90% probability of attaining the bactericidal target for PIPC (50% T > MIC) in prostate tissue. However, against Pseudomonas aeruginosa isolates, none of the tested regimens achieved a >90% probability. PIPC-TAZ is appropriate for the treatment of prostatitis from the site-specific PK-PD perspective.

Clinical pharmacokinetics of meropenem in pancreatic juice and site-specific pharmacodynamic target attainment against Gram-negative bacteria: dosing considerations.

BACKGROUND AND OBJECTIVE: Very few studies have revealed the dynamics of meropenem penetration into the pancreas or pancreatic juice in humans. This study of the clinical pharmacokinetics and pharmacodynamics of meropenem in human pancreatic juice was performed to establish a basis for the validation of dosing regimens for pancreatic infections. METHODS: Ten patients with endoscopic naso-pancreatic drainage received 500 mg meropenem over 0.5 h via intravenous infusion. Venous blood and pancreatic juice samples were collected post-infusion for up to 5.0 h and used to obtain measures of meropenem concentration. The probability of attaining the pharmacodynamic target (40% of the time above the minimum inhibitory concentration [MIC]) in pancreatic juice against MIC distributions for clinical isolates of Gram-negative bacteria was determined using a Monte Carlo simulation. RESULTS: The mean maximum concentration of meropenem in pancreatic juice was 2.08 ± 0.94 µg/mL at 1.025 ± 0.18 h. The pancreatic juice/plasma ratio was 0.055 ± 0.028. A 0.5-h infusion of 500 mg meropenem every 8 h achieved a 99.4% probability of target attainment against Escherichia coli, 96.4% against Klebsiella species, 94.3% against Enterobacter species and 96.2% against Proteus species, but only 41.3% against Pseudomonas aeruginosa isolates. CONCLUSION: Intravenous meropenem exhibits low penetrance into pancreatic juice. However, a dosing regimen of 500 mg meropenem (0.5-h infusion) every 8 h provides sufficient drug-exposure time in pancreatic juice against the four common Gram-negative bacteria populations.

Factors affecting treatment and recurrence of Clostridium difficile infections.

The antimicrobial agents vancomycin and metronidazole have been used to treat Clostridium difficile infections (CDIs). However, it remains unclear why patients are at risk of treatment failure and recurrence. Therefore, this study retrospectively examined 98 patients with CDIs who were diagnosed based on the detection of toxin-positive C. difficile to determine the risk factors affecting drug treatment responses and the recurrence of CDI. No significant difference was observed in the cure rate or dosage between the vancomycin and metronidazole groups. The 90-d mortality rate and total number of drugs associated with CDIs, including antiinfective agents used within 2 months before the detection of toxin-positive C. difficile, were significantly lower in the treatment success group than in the failure group. The total number of antiinfective agents and gastric acid-suppressive agents used during CDI therapy was also significantly lower in the success group than in the failure group. The period from the completion of CDI therapy to restarting the administration of anticancer agents and steroids was significantly longer in patients without than in patients with recurrence. These results indicate that the total number of drugs associated with CDIs should be minimized to reduce the risk of CDIs, that not only antibiotics but also gastric acid-suppressive agents should be discontinued during CDI therapy to increase therapeutic efficacy, and that the use of anticancer agents and steroids should be delayed as long as possible after patients are cured by CDI therapy to prevent recurrence.

Nephrotoxicity induced by piperacillin­tazobactam in late elderly Japanese patients with nursing and healthcare associated pneumonia.

This study aimed to clarify the efficacy, safety, and pharmacokinetics of piperacillin­tazobactam (PIPC­ TAZ) in late elderly Japanese patients. This is the first antimicrobial pilot study in late elderly patients with nursing and healthcare associated pneumonia. After PIPC­TAZ administration, PIPC concentrations in plasma were measured chromatographically and the pharmacokinetic parameters were estimated. Efficacy, safety, and bacteriological evaluations were also carried out. The mean age was 85.0 years old and most of the patients were late elderly. Chest X-rays, body temperature, white blood cell count, and C reactive protein all improved significantly, and a high efficacy ratio of 90.9% was observed. Serious nephrotoxicity was observed in 4 cases (18.2%) after administration of PIPC­TAZ. Creatinine clearance (meanS.D.) measured before PIPC­TAZ therapy was significantly lower in the nephrotoxicity group (32.54.4 mL/min) than in the non-nephrotoxicity group (46.116.7 mL/min), although the ages were not different between the 2 groups. In the pharmacokinetic parameters for PIPC, total clearance was slightly lower in the nephrotoxicity group than in the non-nephrotoxicity group. However, no significant difference was observed in plasma PIPC levels between the 2 groups. In patients with renal impairment, especially with a creatinine clearance of <40 mL/ min, renal impairment was found to be an influencing factor for severe nephrotoxicity following PIPC­TAZ administration. In conclusion, the results suggest that physicians should pay close attention in order to avoid possible toxicity, and that deliberate administration planning and careful follow-up are required in late elderly patients with comprised organ dysfunction.