山崎 伸吾

Introduction. The aim of this study was to evaluate the practicality of the signal transducer and activator of transcription (STAT) 3 polymorphisms as a predictive biomarker and sorafenib trough concentration as a monitoring biomarker for hand-foot skin reaction (HFSR) in patients with hepatocellular carcinoma (HCC). Methods. In total, 43 Japanese HCC patients were included. Sorafenib concentrations were measured, if possible, on days 8, 29, 35, and 57. The sorafenib concentration on day 8 (Cday8) was used for the analysis of HFSR occurring up to day 29. The median concentration for each patient (Cmedian) was used for HFSR occurring up to day 57 (study period). The STAT3 single nucleotide polymorphism (SNP) rs4796793 was determined using cell-free DNA extracted from plasma. Result. The Cday8 tended to be higher in the HFSR onset or grade ≥ 2 HFSR severity group than in the non-HFSR or grade ≤ 1 HFSR severity group. The Cmedian was significantly higher in the HFSR onset or grade ≥ 2 group than in the non-HFSR or grade ≤ 1 HFSR group. The Cmedian thresholds for predicting HFSR onset and severity were 3.62 μg/mL and 6.10 μg/mL, respectively. There was no association between STAT3 rs4796793 and HFSR onset or severity. In multivariate analysis, Cmedian values ≥ 3.62 μg/mL and >6.10 μg/mL were associated with the increased risk of HFSR onset (odds ratio: 16.6, p < 0.01) and severity (odds ratio: 15.7, p < 0.01), respectively. Conclusion. Monitoring of the sorafenib trough concentration may be practical for avoiding HFSR.

OBJECTIVES: The pharmacokinetics of vancomycin and meropenem in patients treated with continuous online hemodiafiltration (OL-HDF) are not well understood. CASE: We evaluated dialytic clearance and serum concentrations of vancomycin and meropenem by OL-HDF in a critically ill patient with soft tissue infection. The mean clearance of OL-HDF and mean serum concentrations during continuous OL-HDF were 155.2 mL/min and 23.1 μg/mL for vancomycin and 145.6 mL/min and 22.7 μg/mL for meropenem. CONCLUSION: Vancomycin and meropenem showed high clearance rates during continuous OL-HDF. However, continuous infusion of these agents at high doses maintained therapeutic serum concentrations.

OBJECTIVES: A marked prolongation of the prothrombin time-international normalized ratio (PT-INR) is frequently observed during biliary obstruction in patients using warfarin. The objective of this study was to identify factors associated with PT-INR prolongation during biliary obstruction in patients using warfarin. METHODS: Among 44 patients using warfarin who had biliary obstruction, we retrospectively investigated warfarin doses and laboratory data before and during biliary obstruction. The primary outcome was the association between changes in PT-INR (ΔPT-INR) and changes in laboratory data before and during biliary obstruction. RESULTS: Median PT-INR was 1.59 (IQR 1.38-1.95) before biliary obstruction and 2.27 (IQR 1.60-3.49) during biliary obstruction, indicating significant prolongation during the obstruction (P < 0.001). ΔPT-INR showed strong positive correlations with change in total bilirubin (ΔT-Bil; ρ = 0.692, P < 0.001) and change in conjugated bilirubin (ΔC-Bil; ρ = 0.731, P < 0.001). ΔPT-INR showed a weak negative correlation with the change in albumin (ΔAlb; ρ =  -0.371, P < 0.05). When ΔPT-INR was used as the dependent variable in multiple linear regression analysis, ΔT-Bil, ΔC-Bil, and ΔAlb were significantly associated with ΔPT-INR. CONCLUSIONS: PT-INR was prolonged during biliary obstruction in patients using warfarin, and changes in bilirubin levels were associated with ΔPT-INR. If biliary obstruction with markedly elevated bilirubin levels occurs, measuring PT-INR could lead to safer warfarin therapy.

INTRODUCTION: The usefulness of smartphone-based application software as a way to manage adverse events (AEs) after vaccination is well known. The purpose of this study is to clarify the usefulness and precautions of employing a smartphone application for collecting AEs after the administration of Comirnaty®️. METHODS: Healthcare workers (HCWs) who were vaccinated with Comirnaty®️ were asked to register for the application software and to report AEs for 14 days after vaccination. AEs were self-reported according to severity. The software was set to output an alert in case of fever. RESULTS: The number of HCWs who received the first dose was 2,551, and 2,406 (94.3%) reported their vaccinations. 2,547 received the second dose, and 2,347 (92.1%) reported their vaccinations. With the first dose, the reporting rate stayed above 83.3% until the final day. On the other hand, that of the second dose decreased rapidly after 6 days. The most frequent symptom was "pain at injection site" (more than 70%). Severe AEs were 6.6% after the second dose, with 0.6% visiting a clinic. Many AEs peaked on the day after administration and disappeared within 1 week. There were few reports of fever. CONCLUSION: Smartphone applications can be used to collect information on AEs after vaccination. Application settings and dissemination are necessary to maintain the reporting rate of HCWs.

BACKGROUND: Voriconazole (VRCZ) is the first-line therapy for chronic pulmonary aspergillosis and is available in both intravenous and oral formulations. The bioavailability of the oral form is estimated to be over 90% in healthy volunteers. Some drugs are reported to interact with enteral nutrition (EN), but there are few reports about the trough levels of VRCZ during EN therapy. Here, we describe changes in the VRCZ trough levels in a patient receiving continuous EN therapy. CASE PRESENTATION: The patient was a 58-year-old man with esophageal cancer and a history of partial pulmonary resection due to aspergilloma. He was taking oral VRCZ tablets and his VRCZ trough level was about 2 μg/mL before esophageal cancer surgery. Following esophagectomy, VRCZ was restarted on postoperative day 16. Crushed VRCZ tablets were administered via a jejunostomy tube because of swallowing difficulty. He was also receiving EN, which was interrupted only during the administration of VRCZ. When we checked his VRCZ level 5 days after restarting VRCZ, the trough level was 0.80 μg/mL. After increasing the VRCZ dose, reducing EN, and changing the administration route from jejunostomy tube to oral, his trough level increased to 1.87 μg/mL. CONCLUSIONS: A decrease in the VRCZ trough level was observed when VRCZ was administered via a jejunostomy tube while the patient was receiving continuous EN. Careful monitoring of VRCZ levels is needed in such cases.

BACKGROUND: The blood concentration of cyclosporine (CyA) is frequently elevated following the transfusion of red blood cell concentrate (RCC) to patients after allogeneic hematopoietic stem cell transplantation (HSCT). The aim of this retrospective study was to identify the variable factors affecting changes in the blood concentration of CyA before and after transfusion of RCC. METHODS: We enrolled 105 patients (age, 5-66 years) who received both CyA and transfusion after HSCT. The ratio of the measurement after transfusion to the measurement before transfusion was calculated for the hematocrit and blood concentration/dose ratio of CyA (termed the HCT ratio and the CyA ratio, respectively). RESULTS: The blood concentration/dose ratio of CyA was increased after transfusion compared with before transfusion (P < 0.001). The HCT ratio was significantly correlated with the CyA ratio (P = 0.23, P < 0.001). The HCT ratio, concomitant medication that could elevate CyA concentration after RCC transfusion, and difference in the alkaline phosphatase level between before and after transfusion (ΔALP) were explanatory variables associated with the variation in the CyA ratio. There was no correlation between the CyA concentration after transfusion and the change in the estimated glomerular filtration rate. CONCLUSIONS: A change in the blood concentration/dose ratio of CyA was found to be associated with a change in the HCT, concomitant medication that could elevate CyA concentration after RCC transfusion, and ALP levels. If the HCT level rises significantly after RCC transfusion, clinicians and pharmacists should pay attention to changes in the blood CyA concentration.

BACKGROUND: Vancomycin (VCM) is eliminated mainly by diafiltration under continuous hemodiafiltration (CHDF), but the contribution of adsorption to CHDF clearance (CLCHDF ) of VCM using a polyacrylonitrile and sodium methallyl sulfonate copolymer membrane coated with polyethylenimine (AN69ST) or a polymethylmethacrylate (PMMA) membrane is unknown. This study sought to investigate the contribution of diafiltration and adsorption to the CLCHDF of VCM using AN69ST and PMMA membranes in vitro. METHODS: An in vitro CHDF circuit model was developed. The initial concentration of VCM was 50 μg/mL and human serum albumin (HSA) was prepared at a concentration of 0, 2.5, or 5.0 g/dL. The effluent flow rate (Qe) was set at 800, 1500, or 3000 mL/h. The CLCHDF , diafiltration rate, and adsorption rate of VCM were calculated. RESULTS: Total CLCHDF of VCM using the AN69ST membrane increased and decreased with increasing Qe and HSA concentration, respectively. Diafiltration and adsorption rates were 82.1 ± 9.8% and 12.1 ± 6.1% under all conditions, respectively. Total CLCHDF using the PMMA membrane increased with increasing Qe. Diafiltration and adsorption rates were 89.2 ± 20.4% and 4.6 ± 17.0% under all conditions, respectively. The observed CLCHDF values significantly correlated with the predicted CLCHDF , calculated according to a previous study as the product of Qe and the plasma unbound fraction. CONCLUSIONS: Diafiltration predominantly contributed to CLCHDF of VCM using AN69ST and PMMA membranes. When diafiltration rather than adsorption mainly contributes to the CLCHDF of VCM, the CLCHDF could be predicted from the Qe and HSA concentration, at least in vitro.

INTRODUCTION: The purpose of this study was to explore factors influencing meropenem pharmacokinetics (PKs) in critically ill patients by developing a population PK model and to determine the optimal dosing strategy. METHODS: This prospective observational study involved 12 critically ill patients admitted to the intensive care unit and treated with meropenem 1 g infused over 1 h every 8 h. Blood samples were collected on days 1, 2, and 5 immediately prior to dosing, and at 1, 2, 4, and 6 h after the start of infusion. Population PK parameters were estimated using nonlinear mixed-effects model software. RESULTS: Meropenem PK was adequately described using a two-compartment model. Typical values of total and inter-compartmental clearance were 9.30 L/h and 9.70 L/h, respectively, and the central and peripheral compartment volumes of distribution were 12.61 L and 7.80 L, respectively. C-reactive protein (CRP) was identified as significant covariate affecting total meropenem clearance. The probability of target attainment (PTA) predicted by Monte Carlo simulations varied according to the patients' CRP. The PTA of 100% time above the minimum inhibitory concentration ≤2 mg/L for bacteria was achieved after a dose of 1 and 2 g infused over 4 h every 8 h in patients with CRP of 30 and 5 mg/dL, respectively. CONCLUSION: The findings of this study suggest that CRP might be helpful in managing meropenem dosing in critically ill patients. Higher doses and extended infusion may be required to achieve optimal pharmacodynamic targets.

Vancomycin (VM) is used as empirical therapy for bacterial meningitis (BM). We investigated the relationship of the microbiological efficacy of VM for BM with VM minimum inhibitory concentration (MICVM), serum VM trough concentration (VMser) and cerebrospinal fluid (CSF) protein (P)/serum albumin (SA) ratio, which may reflect the extent of blood-brain barrier (BBB) disruption. Twelve BM patients were enrolled and VM was microbiologically effective in seven (58.3%). VMser, MICVM, and CSF-P/SA ratio were not associated with the microbiological efficacy of VM. The microbiological efficacy of VM was significantly associated with CSF-P/SA ratio multiplied by VMser relative to the MICVM (η = 0.61, p = 0.04). These results indicate that the parameter combining VMser, MICVM, and the extent of BBB disruption could be associated with the microbiological efficacy of VM in BM patients.

病院薬局製剤(以下、院内製剤)の使用においては、使用患者の把握や有効性・安全性の評価が求められている。しかし、手術部で使用されるピオクタニン製剤については、多くの施設において外科系診療科により汎用される一方で、その適正な管理体制に関する報告はない。千葉大学医学部附属病院では管理適正化を目的として、医師に1%滅菌ピオクタニン液の代替市販品を周知し、手術部門システムを改修し使用の記録を必須とした。2018年の周知後、2019年に払い出した1%滅菌ピオクタニン液は半減し、その使用は市販品で代替の利かない症例に限定された。また、システム改修により、使用患者を全例把握することができるとともに、医師による有効性・安全性評価の報告が可能となった。今回の介入法を用いることで、手術部におけるピオクタニン製剤のように多診療科で多患者に使用する院内製剤に関しても、適正に管理できることが明らかとなった。(著者抄録)

The efficacy of pharmacokinetically (PK) guided, once-daily administration of busulfan (BU) was evaluated in elderly patients with acute myeloid leukemia/myelodysplastic syndrome (AML/MDS). Twenty-one patients (median age 61) received 30 mg/m2 fludarabine for 6 days and BU for 4 days, starting from 3.2 mg/m2 and subsequently adjusted to the target area under the curve (AUC) of 6000 µmol-min/L. The median AUC of day 1 (AUC1), AUC4, and their average were 4871.3, 6021.0, and 5368.1 µmol-min/L, respectively. Veno-occlusive disease/sinusoidal obstructive syndrome (VOD/SOS) occurred in five patients (24%) but all recovered well. Four patients (20%) had non-infectious pulmonary complications (NIPCs). Patients with high AUC1 had frequent gastrointestinal adverse events, but similar incidence of VOD/SOS and NIPCs. Two-year overall survival (OS), non-relapse mortality (NRM), and relapse rates were 44.4%, 28.6%, and 29.1%, respectively. Patients with high AUC1 had significantly high NRM (57.1% vs. 14.3%, P = 0.04) and inferior OS (14.3% vs. 60.1%, P = 0.002), while patients with high AUC4 had a significantly low relapse rate (8.3% vs. 55.6%, P = 0.02). In conclusion, once-daily BU and a PK-guided dose intensification were beneficial for reducing relapse in elderly patients with AML/MDS. However, caution should be exercised as rapid BU dose elevation may contribute to NRM.

When transplacental therapy is conducted, the maternal serum concentrations of digoxin and flecainide may fluctuate throughout third trimester. Therefore, TDM may be effective in improving the efficacy and safety of treatment.

WHAT IS KNOWN AND OBJECTIVE: The removal rates of tacrolimus (TAC) and mycophenolic acid (MPA) by simultaneous plasma exchange (PE) and continuous hemodiafiltration (CHDF) are not clear. CASE SUMMARY: We evaluated the removal rates of TAC and MPA by PE and CHDF started simultaneously 5 hours after administration in a lung transplant patient. TAC was not removed. MPA was transferred into the PE effluent, but the total amount in the effluent was only 1% of the dosage. WHAT IS NEW AND CONCLUSION: TAC and MPA were less likely to be removed by PE and CHDF initiated 5 hours after administration.

OBJECTIVE: Japan is an aging society, and pneumonia is the leading cause of death, but the suitability of antibiotics for treating community-acquired pneumonia (CAP) in Japan is not clear. The purpose of this study was to investigate antibacterial drugs for treating CAP according to age. MATERIALS AND METHODS: Using the Japanese national database from 2011 to 2014, we analyzed the usage of antibiotics for CAP according to age. RESULTS: The numbers of claim information were 9,386, and 70% of the patients were aged ≥ 75 years. Sulbactam/ampicillin (SBT/ABPC) or ceftriaxone (CTRX) was used in 60%, but broad-spectrum antibiotics, combination therapy, and anti-mycoplasma antibiotics were used in 15 - 28% of all age groups. The 30-day survival rate did not differ between SBT/ABPC or CTRX vs. others. There was no difference in 30-day mortality and risk in any group between the ages of 15 and 64 years. On the other hand, the use of anti-mycoplasma antibiotics reduced the 30-day mortality by 0.50 times (p < 0.01), and the use of two or more antibiotics increased the 30-day mortality by 1.45 times (p = 0.02) at age ≥ 65 years. CONCLUSION: Approximately half of the antibiotics used for CAP requiring hospitalization consisted of CTRX or SBT/ABPC as recommended by the Japanese Respiratory Society (JRS) guidelines. On the other hand, the usage of broad-spectrum antibiotics and combination therapy were relatively frequent at all ages, although their use does not always contribute to survival. Our data provide basic information for analyzing the outcome of pneumonia treatment in terms of an antimicrobial resistance action plan in Japan.

INTRODUCTION: Community-acquired pneumonia (CAP) is one of the most common causes of pediatric infection requiring hospitalization. Antimicrobial resistance due to the inappropriate use poses a threat worldwide. Our objective is to analyze and optimize the trends of antibiotics used for pediatric inpatients with CAP in a claims database provided by the Ministry of Health, Labour and Welfare. METHODS: Our database randomly sampled 10% of the hospitalized patients every October from 2011 to 2014. Patients aged <15 years in whom antibiotic therapy was initiated within two days of admission were listed. Subsequently, we investigated the antibiotics administered on the first day of prescription. RESULTS: A total of 4,831 antibiotics were prescribed for 3,909 patients. Many patients aged ≤ five years were treated with β-lactams alone whereas many patients aged ≥ six years were treated with a single antibiotic, such as a macrolide, tetracycline, and quinolone, which covers atypical bacteria. Combination therapy was primarily used in children aged ≥ six years (nearly 30%); the main combination was a β-lactam and non-β-lactam covering atypical bacteria. Ampicillin-sulbactam was the most frequently prescribed β-lactam in children of all ages other than infants. Ampicillin, however, was most often prescribed in infants, but its usage rate was low at other ages. CONCLUSIONS: Antibiotics were appropriately prescribed and were similar to that recommended in the 2011 guidelines for pediatric inpatients with CAP. However, combination therapy was frequently prescribed in children aged ≥ six years. According to the revised guidelines in 2017, ampicillin should be used more frequently for patients hospitalized with CAP.

Favipiravir is an antiviral drug that is expected to have a therapeutic effect on SARS-CoV2 infection. Teratogenicity and hyperuricemia are known as the main side effects of favipiravir, but little is known about other side effects. This report describes a case of cholestatic liver injury induced by favipiravir. A 73-year-old Japanese with a history of alcoholic hepatitis was infected with SARS-CoV2. Drug therapy was instituted with lopinavir/ritonavir combined with interferon β-1b. However, his condition worsened despite additional support with continuous hemodiafiltration and veno-venous extracorporeal membrane oxygenation. We suspected complications of bacterial pneumonia and started favipiravir in addition to antimicrobial therapy. Favipiravir was administered at 6000 mg/day on the first day and 2400 mg/day for the second and subsequent days for 14 days. After the initiation of antibiotics, transaminase and total bilirubin were elevated, suggesting a transient cholestasic liver dysfunction. The liver dysfunction in this case may have been triggered by antibacterial treatment, and high dose of favipiravir may have promoted the deterioration of liver function. Monitoring of liver function is vital and close attention should be paid when using favipiravir at high doses or in patients with impaired liver function.

Survival Sepsis Campaign (SSC) guidelines have recommended broad-spectrum antibiotics prescriptions to cover the possible pathogenic microorganisms. However, mortality from sepsis is still high, as about one quarter of cases are thought to result in death. We analyzed nationwide health claims data of universal health insurance systems in Japan. Our aim was to describe the antibiotics prescriptions and underlying conditions of Japanese sepsis patients. In addition, we analyzed the factors associated with 30-day mortality. A total of 1188 patients aged ≥15 years were entered, of which 80.1% were ≥65 years old. Broad-spectrum antibiotics were prescribed for 53.8%. Carbapenem, Piperacillin Tazobactam and Anti-pseudomonas Cephalosporin were prescribed for 30.8%, 13.0% and 12.2% of the patients, respectively. (Some patients were counted twice) The overall 30-day mortality rate was 21.3%. Risk factors associated with 30-day mortality were examined by Cox proportional hazards regression analysis. Age of ≥85 years, malignancy, chronic kidney disease (CKD), shock and respiratory failure were selected as risk factors, but broad-spectrum antibiotics was not included. Sepsis is mostly observed in those aged 65 years and over. The rates of broad-spectrum antibiotics were restricted, and antibiotics were also not necessarily prescribed on the basis of SSC guidelines. However, broad-spectrum antibiotics did not improve the treatment outcome. Aging and underlying conditions like malignancy, CKD, shock and respiratory failure were poor prognostic factors.

千葉大学医学部附属病院では2016年4月から病院薬局製剤(以下、院内製剤)の使用患者の調査と医師による有効性および安全性の評価を行っている。本研究では2018年12月までを対象に院内製剤のクラス分類、投与経路、診療科、管理方法と有効性および安全性評価の実施の関連を明らかにすることを目的とした。全体の74.9%の製剤に対し有効性および安全性の評価が行われていた。クラス分類、投与経路、診療科、管理方法により評価実施率は異なった。いずれの因子も評価の実施との関連がみられたが、因子間の関連が強く各因子の影響の大きさは不明だった。しかし、使用患者の事前把握やストックの有無、分割使用といった管理方法とそれらの組み合わせが影響する可能性が示されたことから、院内製剤の有効性および安全性評価を実施するために、薬剤師は主体的に管理体制構築にかかわる必要があると考えられた。(著者抄録)

BACKGROUND: The aim of this study was to conduct a population pharmacokinetic (PK) analysis of meropenem and to explore the optimal dosing strategy for meropenem in critically ill patients with acute kidney injury receiving treatment with continuous hemodiafiltration (CHDF). METHODS: Blood samples were obtained on days 1, 2, and 5 after the start of meropenem administration, immediately before dosing, and at 1, 2, 6, and 8 hours after dosing. Population PK model analysis was performed and concentration-time profiles were simulated using the Nonlinear Mixed Effects Model software. RESULTS: Twenty-one patients receiving CHDF in our intensive care unit were enrolled and 350 serum concentration-time data points were obtained. The PKs of meropenem were best described using a 2-compartment model. Typical total and intercompartmental clearance values were 4.22 L/h and 7.84 L/h, respectively, whereas the central and peripheral compartment volumes of distribution were 14.82 L and 11.75 L, respectively. Estimated glomerular filtration rate was identified as a significant covariate of meropenem total clearance. In simulations of patients with renal failure receiving CHDF, the dose was affected by estimated glomerular filtration rate; a dose of 0.5 g every 8 hours or 1 g every 12 hours showed the probability of target attainment of achieving 100% time above the minimum inhibitory concentration for bacteria with a minimum inhibitory concentration ≤2 mg/L. CONCLUSIONS: A population PK model was developed for meropenem in critically ill patients with acute kidney injury receiving CHDF. Our results indicated that a meropenem dosage of 0.5 g every 8 hours or 1 g every 12 hours was suitable in this population and for susceptible bacteria.

WHAT IS KNOWN AND OBJECTIVE: Vitamin K deficiency is known to cause impaired coagulation. We report a case of marked prolongation of the prothrombin time-international normalized ratio (PT-INR) associated with warfarin and vitamin K deficiency caused by endoscopic nasobiliary drainage (ENBD). CASE PRESENTATION: Oral administration of warfarin was initiated in a 67-year-old man after left hemihepatectomy. He developed a biliary fistula after surgery that was treated by ENBD, which resulted in significant prolongation of the PT-INR. WHAT IS NEW AND CONCLUSION: The effect of warfarin was enhanced in this patient due to reduced absorption of vitamin K as a result of external biliary drainage.

Aspergillus empyema is treated with either systemic administration of antifungal drugs or surgery, but the mortality rate is very high. Here, we report a case of Aspergillus empyema successfully treated using combined intrathoracic and intravenous administration of voriconazole (VRCZ). Treatment success was achieved by monitoring VRCZ plasma trough concentration. The patient was a 71-year-old Japanese woman diagnosed with Aspergillus empyema whom we started on intravenous administration of VRCZ. Although penetration of VRCZ into the pleural effusion was confirmed, the level was below 1 μg/mL, which is the minimum inhibitory concentration for Aspergillus fumigatus determined by antifungal susceptibility testing in pleural effusion culture. Therefore, we initiated combination therapy with intrathoracic and intravenous administration of VRCZ. VRCZ 200 mg was first dissolved in 50-100 mL of saline and administered into the thoracic cavity via a chest tube. The chest tube was clamped for 5-6 h, and then VRCZ solution was excreted though the chest tube. When a single dose of the VRCZ was administered into the intrathoracic space, the plasma concentration before intravenous administration increased from 1.45 μg/mL on day 27 to 1.53 μg/mL on day 28. Although intravenous administration was continued, the VRCZ plasma trough concentration decreased to 1.36 μg/mL on day 29. We therefore decided on an intrathoracic administration schedule of 2-3 times a week. Intrathoracic administration was performed 14 times in total until fenestration surgery on day 64. Our case suggests that combined intrathoracic and intravenous administration of VRCZ may be a valid treatment option for Aspergillus empyema.

BACKGROUND: Although continuous hemodiafiltration (CHDF) is often performed in critically ill patients during sepsis treatment, the pharmacokinetics of vancomycin (VCM) during CHDF with a polymethylmethacrylate hemofilter (PMMA-CHDF) have not been revealed. In this study, the authors aimed to describe the population pharmacokinetics of VCM in critically ill patients undergoing PMMA-CHDF and clarify its hemofilter clearance (CLhemofilter). METHODS: This single-center, retrospective study enrolled patients who underwent intravenous VCM therapy during PMMA-CHDF at the intensive care unit of Chiba University Hospital between 2008 and 2016. A population analysis was performed, and CLhemofilter was assessed. RESULTS: Twenty-five patients were enrolled. Median body weight (BW) and Sequential Organ Failure Assessment (SOFA) score were 63 kg and 15, respectively. Mean conditions for CHDF were 107.5 ± 18.3 mL/min for blood flow rate and 26.3 ± 6.3 mL/kg/h for effluent flow rate. The mean parameter estimates were distribution volume of the central compartment (V1), 59.1 L; clearance of the central compartment (CL1), 1.35 L/h; distribution volume of the peripheral compartment (V2), 56.1 L; and clearance of the peripheral compartment (CL2), 3.65 L/h. BW and SOFA score were significantly associated with V1 (P < 0.05) and CL1 (P < 0.05), respectively, and were thus selected as covariates in the final model. The estimated dosage of VCM to achieve a target area under the concentration-time curve/minimum inhibitory concentration ≥400 was 27.1 mg/kg for loading and 9.7 mg/kg every 24 hours for maintenance; these dosages were affected by BW and SOFA score. Mean CLhemofilter obtained from 8 patients was 1.35 L/h, which was similar to CL1. CONCLUSIONS: The authors clarified the pharmacokinetics and CLhemofilter of VCM in PMMA-CHDF patients. The PK of VCM in patients undergoing CHDF appeared to vary not only with the CHDF setting and BW but also with SOFA score.

Background Elevated blood concentration of tacrolimus is frequently observed following transfusion of red blood cell concentrate in patients after allogeneic hematopoietic stem cell transplantation. Objective The aim of this retrospective study was to clarify the effects of transfusion of red blood cell concentrate on the blood concentration of tacrolimus. Setting Chiba University Hospital in Japan. Method Fifty-two patients (aged 0-65 years) receiving both tacrolimus and transfusion after allogeneic hematopoietic stem cell transplantation were enrolled. The ratio of measurement after transfusion to measurement before transfusion was calculated for hematocrit and blood concentration/dose ratio of tacrolimus (termed the hematocrit ratio and the tacrolimus ratio, respectively). Main outcome measure Change in blood concentration/dose ratio of tacrolimus and variable factors associated with variation in tacrolimus ratio. Results The blood concentration/dose ratio of tacrolimus was increased after transfusion compared with before transfusion (p < 0.001). A statistically significant correlation was seen between the hematocrit ratio and tacrolimus ratio (r = 0.32, p < 0.001). Hematocrit ratio, age or body surface area, and difference in aspartate aminotransferase level before and after transfusion were associated with the variation in tacrolimus ratio. There was no correlation between tacrolimus ratio and change in serum creatinine or potassium level in the short term. Conclusion Change in the blood concentration/dose ratio of tacrolimus was associated with change in the hematocrit ratio after transfusion, and more attention is required for children or patients with small body surface area. Dose adjustment of tacrolimus is required if the blood concentration of tacrolimus is much higher than the target concentration.

The Macrolides (MLs), clarithromycin and azithromycin, are key drugs for non-tuberculous mycobacteria (NTM) diseases treatment. A three antibiotics regimen including MLs, rifampicin (RFP) and ethambutol (EB) has been recommended for the treatment of NTM diseases in ATS/IDSA guideline. However, anti-biotics are not necessarily prescribed in compliance with the guideline. Inappropriate regimens are risk of introducing MLs resistance. Therefore, we planned this study to evaluate the current Japanese NTM diseases treatment conditions. We used the national database (NDB) from 2011 to 2014. A total of 183 patients were entered into the study. The patients number increased at an accelerating rate in patients aged ≥55 years. Patients aged ≥55 years made up 91.3% of the total NTM diseases. Male and female patients were 61 and 122, respectively, a female/male ratio of 2.00. Clarithromycin, RFP, EB and fluoroquinolones were frequently prescribed, with the numbers of prescriptions being 125, 66, 57 and 45, respectively. The regimen of MLs, RFP and EB recommend by ATS/IDSA guideline 2007 was only followed by 25.1% of the patients. MLs monotherapy was as high as 30.6% of NTM diseases and would be a risk factor leading to an increase of MLs resistance and poor treatment outcome. Without effective NTM disease therapy, the increase of MLs-resistant NTM diseases would be a burden for Japanese health care facilities.

Aspergillosis is a rare fungal infection in newborns, and its morbidity and mortality are high. Voriconazole (VRCZ) is the first-line antifungal agent for invasive Aspergillus infection, but little data is available about its pharmacokinetics in infants. We report a case of a premature infant who developed ventriculitis due to Aspergillus fumigatus and received combination antifungal therapy including VRCZ. β-D glucan and Aspergillus antigen index were elevated in the cerebrospinal fluid (CSF). We titrated the dose of VRCZ by monitoring plasma and CSF concentrations. The CSF to plasma concentration ratio of VRCZ ranged from 0.47 to 1.36 (median 0.71). While VRCZ adequately penetrates the blood-brain barrier, its concentration is highly variable in infants.

Pneumonia is the third leading cause of death in Japan. Mortality increases at an accelerating rate in elderly patients aged ≥65 years. Elderly patients tend to have underlying conditions affecting pneumonia treatment. The national database (NDB) associated with medical services under Japanese universal health insurance is available for research purposes. Our NDB randomly sampled 10% of hospitalized patients every October from 2011 to 2014. In this NDB, we analyzed pneumonia epidemiology in patients aged ≥15 years and 30-day mortality in Japanese hospitals. This study also investigated the factors affecting treatment outcome. A total of 9386 patients were entered. The number of patients from age 65 years and older increased greatly, representing 85% of the total. The thirty-day mortality rate among all patients was 11.7%. Mortality rates at age 15-64, 65-74, 75-84, and ≥85 years were 9.5%, 12.0%, 8.3%, and 14.9%, respectively, showing significant differences (P < 0.001). The underlying conditions varied among age groups. Male gender, age, heart failure, chronic kidney disease (CKD), consciousness disorder, shock and respiratory failure are risk factors for 30-day mortality. Pneumonia develops mainly in people aged 65 years and older in Japan, and treatment outcome is generally poor in elderly patients. The underlying conditions were seen to affect the 30-day mortality rate. CURB-65 and ADROP, a modification of CURB-65 in Japan, have already estimated these risk factors, and heart failure and CKD might be additional factors for estimating pneumonia severity.

WHAT IS KNOWN AND OBJECTIVE: We conducted a pilot clinical trial to investigate whether Hangeshashinto (TJ-14) could be substituted for oral alkalization in patients scheduled to undergo chemotherapy by FOLFIRI.3 regimen for colorectal cancer (CRC). METHODS: Patients with CRC were randomized 1:1 to a TJ-14 (7.5 g/day) group or an oral alkalization (sodium bicarbonate, 1.8 g/day; ursodeoxycholic acid, 300 mg/day) group. The primary endpoint was incident of late-onset diarrhoea. A total of 30 patients were randomized to either the TJ-14 group or the alkalization group. RESULTS AND DISCUSSION: There was no statistical difference in age, concomitantly used drugs or UGT1A1 genotypes between the groups. In the alkalization group (n = 15), the frequency of grade 0/1/2 and grade 3 diarrhoea was 73% and 27%, respectively. In the TJ-14 group (n = 14), the frequency of grade 0/1/2 and grade 3 diarrhoea was 79% and 21%, respectively. Grade 4 diarrhoea was not observed in either group. There was no statistically significant difference in other adverse events or in response to FOLFIRI.3 between the groups. WHAT IS NEW AND CONCLUSION: This pilot trial suggests that TJ-14 is a promising alternative treatment option to reduce FOLFIRI.3-induced late-onset diarrhoea, although additional clinical study with a larger number of patients is necessary to confirm these results.

WHAT IS KNOWN AND OBJECTIVE: Determination of phenobarbital (PB) dosing during continuous haemodiafiltration (CHDF) requires evaluation of both the patient's own clearance and CHDF clearance. CASE DESCRIPTION: Systemic clearance of PB in a 9-year-old female patient with Dravet syndrome, who was undergoing CHDF, was calculated by the Sawchuk-Zaske method, and clearance by CHDF was calculated as the difference between PB levels in influx and efflux, adjusted for the blood purification conditions. Dosage adjustment produced seizure control. WHAT IS NEW AND CONCLUSION: Adjusting PB dose by evaluating the patient's own PB clearance as well as that by CHDF resulted in accurate control of PB level and a reduction in the occurrence of seizures.

Bacterial meningitis is a life-threatening condition. Vancomycin (VCM) is one of the antibiotics used as empirical therapy for bacterial meningitis. It is essential to maintain an adequate concentration of VCM in cerebrospinal fluid (CSF) to treat bacterial meningitis effectively. VCM administered intravenously must pass the blood-brain barrier (BBB) to enter the CSF and the extent of VCM penetration into CSF varies widely among patients. Previous report indicated that CSF albumin level is useful for estimation of VCM CSF penetration. However, CSF albumin level is not measured in routine practice. We focused on CSF protein concentration that is generally examined at the beginning of diagnosis and treatment of bacterial meningitis. We examined the relationship between CSF protein concentration/serum albumin ratio and the extent of VCM penetration into CSF. This retrospective study involved 7 patients admitted to our hospital who were treated with VCM for suspected bacterial meningitis. The VCM concentrations in serum and CSF were 17.6 ± 7.2 μg/mL and 3.31 ± 3.14 μg/mL, respectively. The serum VCM concentrations showed no significant correlation with CSF VCM concentrations. On the other hand, the protein concentration in CSF/serum albumin ratio showed a strong positive correlation with the VCM CSF/serum ratio (r = 0.877, p < 0.005). Our study indicates that the ratio of CSF protein concentration/serum albumin is likely useful for estimating the approximate VCM CSF/serum ratio. This could contribute to an improvement in the treatment of bacterial meningitis.

Inactivated quadrivalent influenza vaccine (IIV4) has been used as seasonal influenza vaccine since 2016 in Japan. This study examined the safety of IIV4 in comparison with the AH1pdm monovalent vaccine used for novel influenza in 2009. Questionnaire surveillance associated with adverse events (AEs) was conducted at Chiba University Hospital, Japan. After being vaccinated, all health care workers (HCWs) were given a daily AEs check sheet on which they recorded solicited events, the same surveillance program used after AH1pdm vaccination in 2009. The frequency of injection site AEs with IIV4 was significantly higher than with the monovalent vaccine, but there was no significant difference with systemic AEs. Injection site and systemic AEs were reported as 83.7% and 25.5%, respectively, with IIV4. The grades of AE, mild, moderate and severe, were 67.2%, 16.4% and 0.1% with IIV4, respectively, indicating that almost all of the AEs reported with IIV4 were mild or moderate. Systemic AEs with IIV4 and monovalent vaccine were reported to be 25.5% and 23.1%, respectively, with the difference not being significant. The grade of AEs with IIV4, mild, moderate and severe, was 19.1%, 5.6% and 0.9%, respectively. The ratio of HCWs reporting AEs peaked at around 80% on day 1, then decreasing to less than 5% by day 7. AEs with IIV4 were reported more frequently compared with the AH1pdm monovalent vaccine. However, in consideration of the grade and duration of AEs, IIV4 was a well-tolerated, safe vaccine.

症例1は40歳代男性で、7年前に糖尿病性腎症による慢性腎不全の精査中にHIV感染症が判明し、抗レトロウイルス療法(cART)を開始した。6年前に維持透析を導入した。通院は不定期で、服薬アドヒアランスおよびHIV-RNA量のコントロールは不良であった。B型肝炎を発症して受診した。cARTが抗HBV作用を持たない核酸系逆転写酵素阻害剤(NRTI)スペアリングレジメンとなっていたこと、アドヒアランス不良の経緯から複雑な服用方法はさらなる治療効果の低下を引き起こすと考えられたこと、透析がすでに導入されていたことから、cARTをツルバダ配合錠(TVD)を用いたNRTIレジメンへ変更した。HIV-RNA量は検出限界以下を維持するとともにCD4数の上昇を認めた。症例2は70歳代男性で、9年前にカンジダ食道炎の診断をきっかけにHIV感染症が判明した。cARTを開始し、HIV-RNA量ならびにCD4数のコントロールは良好であったが腎機能低下を認めた。慢性腎不全の進行により血液透析を導入した。HBs抗体陽性であることを考慮してNRTIをTVDへ変更した。CD4数は上昇し、HIV量は検出限界以下を維持した。

ゲル化基剤として、セルロース誘導体の中から調製が簡便で優れた潤滑性と保水性を有するヒドロキシプロピルメチルセルロース(HPMC)を選択し、その含量を変化させた時のチモロールの放出性、展延性、皮膚透過性、保存性について比較検討した。HPMC濃度は、2.0(w/v)%(L-g)、4.5(w/v)%(M-g)、7.0(w/v)%(H-g)とした。30分、60分、120分、240分の放出濃度において、L-gはH-gに対して有意に高く、平均溶出時間(MDT)も短かった。M-gの測定時間毎の放出濃度とMDTはL-gやH-gと比較して有意差はなかった。平行板粘度計による展延性の結果では、基剤濃度が小さい程傾きが大きく伸びやすかった。健常皮膚モデルであるメンブレンを用いた皮膚透過性試験における6時間後の透過濃度は1.3μg/mLで、セルロース膜を用いたM-g放出試験6時間後の濃度の約0.7%であった。M-gについて、調製直後と4℃で6週間保管した製剤の放出試験を行い、測定時間毎の放出濃度に有意差はなく、その挙動に変化はなかった。

Because there is little absorption of orally administered vancomycin hydrochloride (VCM) through the normal intestinal microvillus membrane, the pharmacokinetics of VCM absorbed from the digestive tract are mostly unknown. Here we report a case of severe colitis and renal insufficiency in which the serum concentration of VCM reached the supratherapeutic range after oral administration. A 54-year-old man receiving outpatient chemotherapy for rectal cancer was admitted to our hospital for severe sepsis and acute renal failure. Multimodal therapy including continuous renal replacement therapy (CRRT) and mechanical ventilation was initiated, and oral VCM administration (0.5 g every 6 h) was begun for suspected severe pseudomembranous colitis with large amounts of watery stool. Despite continued CRRT, the serum VCM concentration increased to 30.6 μg/mL after 4 days. Based on pharmacokinetic analysis, the bioavailability of VCM was estimated to be over 54.5%. Colonoscopy showed that the mucosa was severely damaged throughout the large intestine, resulting in considerable exudation of plasma and blood. This case indicates the need for careful and early monitoring during high-dose oral VCM administration to patients with severe mucosal injury and renal insufficiency.

INTRODUCTION: Recombinant human soluble thrombomodulin (rTM) is reportedly excreted by the kidneys; therefore, the recommended dose for patients with renal impairment is one-third of the standard dose. The aim of this study was to evaluate whether this reduced dose of rTM achieves effective drug concentrations that are comparable to those of the standard dose in treating sepsis-induced disseminated intravascular coagulation (DIC) during continuous hemodiafiltration (CHDF). METHODS: Eight patients in an intensive care unit were randomized to receive either reduced-dose (0.02 mg/kg, n = 4) or standard-dose (0.06 mg/kg, n = 4) rTM. We evaluated the effect of standard dose in comparison to that of reduced dose on the pharmacokinetics (PKs) of rTM for the sepsis-induced DIC patients receiving CHDF. Patients received rTM during a 30-min infusion for six consecutive days. PK parameters of rTM were analyzed using the one-compartment model. RESULTS: The elimination half-life, clearance (T1/2), and distribution volume of sTM were similar between the reduced and standard doses. The maximum concentration (Cmax) and area under the concentration-time curve (AUC) of sTM were approximately 2.5 times higher with standard-dose daily infusions than that with reduced-dose drip infusions (p = 0.041 and 0.062, respectively). The time when the blood concentration of sTM was >500 ng/mL, i.e., the holding time, was significantly longer with standard-dose infusions than those with reduced dose (p = 0.039). CONCLUSION: rTM displayed dose-dependent PK behavior at clinically relevant doses. During CHDF, effective blood concentration of rTM was not achieved with the reduced dose, and rTM was found to not bioaccumulate. Therefore, this pilot study suggests that reducing the rTM dose is unnecessary, even in sepsis-induced DIC patients who require CHDF. However, we need to perform a definitive study to determine the dosage of rTM for the case.

PURPOSE: Although vancomycin (VCM) is not absorbed from healthy intestinal mucosa, elevations in the serum VCM concentrations have been reported in some cases. The aims of this study are to evaluate the necessity of therapeutic drug monitoring (TDM) during enteral VCM administration in critically ill patients. MATERIALS AND METHODS: In this retrospective study, we enrolled 19 patients admitted to our intensive care unit who were treated with enteral VCM from December 2006 to January 2014. Clinical factors were compared between two groups: Group E whose serum concentrations were detectable, and Group N whose concentrations were below the detection limit of the VCM assay. RESULTS: Group E comprises 7 patients, and Group N comprises 12 patients. The fasting duration in Group E was significantly longer compared with that in Group N (17 vs. 8 days, p = 0.023). Furthermore, there was a significant correlation between the serum VCM concentrations and the fasting duration (r = 0.79, p < 0.0001), and the amount of diarrhea (r = 0.46, p = 0.046). No difference was observed in the amount of diarrhea at the time of TDM (Group E; 1,850 mL vs. Group N; 210 mL, p = 0.055) and in the Sequential Organ Failure Assessment subscore for the renal system at the time of TDM (Group E; 4.0 vs. Group N; 1.5, p = 0.068). CONCLUSION: Long durations of fasting and massive diarrhea were associated with elevations in the serum VCM concentrations, which suggested that TDM might be necessary during enteral VCM administration in critically ill patients. TRIAL REGISTRATION: UMIN Clinical Trials Registry identifier UMIN000016955.

造血幹細胞移植後にシクロスポリンA(CyA)の24時間持続点滴を受けた患者50名(男29名、女性21名、16〜62歳)を対象に、腎障害発現頻度とその危険因子について検討した。腎障害グレード2以上に分類されたのは26名であった。平均CyA血中濃度と最大血清クレアチニン値(Cre)との間に相関関係はみられなかった。危険因子について単変量解析を行い、更に解析した項目に関して多重ロジスティック回帰分析を行った結果、腎障害の有意な要因は女性、移植前処置を骨髄破壊的に行った患者、年齢(加齢)であった。また、最大Cre上昇率を用いて腎障害の要因を解析した重回帰分析の結果からは、腎障害の有意な要因は見出せなかった。

我々は、蛍光眼底造影検査(FAG)後の患者の蛍光偏光免疫測定(FPIA)法による血中シクロスポリン(CYA)濃度測定において、バックグラウンドの異常高値により測定不能となった症例を経験した。その原因として、FAGの際に投与された蛍光眼底造影剤フルオレセイン(F)による影響が疑われたため、FPIA法によるCYA、カルバマゼピン(CBZ)および酵素免疫測定法(MEIA法)によるジゴキシン(DIG)濃度測定に及ぼすFの影響について検討を行った。その結果、CYAでは全血液中F濃度が31.25ng/mLまで、CBZでは血清中F濃度は0.5μg/mLまでは薬物の測定値に影響することなく測定可能であったが、この濃度を超過すると測定不能となった。一方、DIGではF濃度が100μg/mLにおいても測定が可能であった。FPIA法による薬物血中濃度測定をFAG実施当日に行う場合には、FAG実施前に採血する必要があると考えられた。(著者抄録)

シクロスポリン(CsA)細粒の分包調剤後の光安定性について検討した。700ルクスの白色蛍光灯による光照射を1日12時間行う条件下において3種の保存形態、分包紙のみで被覆のない状態(曝光保存)、外面がパルプで内面をポリエチレンコーティングされた薬袋内に保管(薬袋内保存)、遮光ポリエチレン袋に保管(遮光袋内保存)で実施した。薬袋内あるいは遮光袋内で保管した場合には3ヵ月までは安定であったが、曝光群においては同様の条件下でCsAの外観が白色に変化し、12週後においてわずかながら規格値である残存率(95%)を下回った。3種の保管環境での溶出パターンの変化について検討し、残存率の低下を反映した溶出率の低下は認めたが、溶出パターンには変化は認めなかった。

BACKGROUND: Tumor lysis syndrome (TLS) is a group of life-threatening metabolic complications that can occur after initiation of cancer chemotherapy. Onset of TLS in the middle of chemotherapy, however, has not been reported previously in patients with hematologic malignancies. OBJECTIVE: We report a case of a patient who experienced TLS of super-acute onset accompanied by hypercytokinemia during chemotherapy treatment with a combination of doxorubicin (Adriamycin), bleomycin, vinblastine, and dacarbazine (ABVD). CASE SUMMARY: A 36-year-old Japanese man (height, 182 cm; weight, 83 kg; body surface area, 2.04 m(2)) was admitted to the hospital for the treatment of malignant lymphoma (clinical stage IVB Hodgkin's lymphoma). Chemotherapy was initiated using the ABVD regimen (doxorubicin [Adriamycin] 25 mg/m(2) by 30-minute infusion, bleomycin 9 mg/m(2) by 30-minute infusion, vinblastine 6 mg/m(2) by bolus injection, and dacarbazine 375 mg/m(2) by 2-hour infusion). During the dacarbazine infusion, the patient's body temperature rose from 36.5 degrees C to 42 degrees C; he experienced a convulsion and then lost consciousness. The convulsion was not suppressed despite the use of diazepam (5 mg IV twice) and phenytoin (500 mg IV). The patient was then transferred to the intensive care unit and sedated using a continuous infusion of midazolam (10 mg/h). Levels of serum lactate dehydrogenase, aspartate aminotransferase, uric acid, blood urea nitrogen, and creatinine evaluated shortly after the ABVD regimen were outside normal limits. In addition, interleukin-6 (IL-6) concentrations were elevated to 54,220 pg/mL. Continuous hemodiafiltration was immediately performed to lower the elevated levels of IL-6. The next day, IL-6 concentrations decreased to 97 pg/mL, and the patient was weaned from ventilator support and sedation. The patient had no adverse effects after the event. According to the results of an assessment using the Naranjo adverse drug reaction probability scale (score = 3), the development of TLS in this patient was possibly related to the chemotherapy regimen. CONCLUSIONS: ABVD chemotherapy was possibly associated with the super-acute onset of TLS in this patient. In addition, hypercytokinemia occurred with TLS, which led to pyrexia, convulsion, and loss of consciousness.

OBJECTIVE: To report a case in which the serum concentration of vancomycin (VCM) reached the supratherapeutic range following oral administration in a patient with severe pseudomembranous colitis and renal insufficiency. CASE SUMMARY: A 65-year-old, 70 kg weighing man with severe acute pancreatitis and acute renal failure was subjected to continuous hemodiafiltration (CHDF). CHDF could only be performed intermittently because of the unstable circulation dynamic of this patient. After admission, intravenous VCM therapy was initiated. Thereafter, oral VCM administration was begun (0.5 g every 6 h). Despite the discontinuation of intravenous VCM after the first 2 days of oral VCM, the serum VCM concentration increased gradually to 49.8 mg/l over a period of 2 weeks from the initiation of oral administration (34.4 mg/l). Based on pharmacokinetic analysis, the bioavailability of VCM was estimated to over 33%. Autopsy findings indicated broadly distributed necrosis on the lamina propria of the mucosa throughout all parts of the intestine below the duodenum. DISCUSSION: This case indicates necessity of the careful monitoring after oral high-dose VCM administration in a patient with a broadly distributed necrosis and renal insufficiency. CONCLUSIONS: TDM should be considered according to renal function, the severity of enteritis and the total dosage of oral VCM administration.

BACKGROUND: The pharmacologic effects of warfarin might be altered by various factors, including drug-drug interaction. CASE SUMMARY: A 49-year-old Japanese man (height, 174 cm; weight, 68 kg) presented with a 20-month history of malignant lymphoma (diffuse large B cell lymphoma, clinical stage IV). He was treated with a combination of rituximab chemotherapy and etoposide, cisplatin, high-dose cytarabine, and methyl-prednisolone (R-ESHAP). He had been receiving warfarin for the secondary prevention of pulmonary embolism with deep venous thrombosis. When R-ESHAP was started, international normalized ratio (INR) increased from 1 to 5. This phenomenon was observed again in the second R-ESHAP. The INR was increased from 2.44 to 4.71 during chemotherapy but was returned to within the normal range (1.05; normal range: 0.81-1.009) 5 days after chemotherapy was completed. CONCLUSION: In this patient, R-ESHAP chemotherapy might have affected warfarin anticoagulation sensitivity; thus, careful monitoring of INR is essential, particularly in patients receiving warfarin who undergo R-ESHAP chemotherapy.