A novel method for predicting the unbound valproic acid concentration.

In this study, we constructed a prediction formula for unbound valproic acid (VPA) concentration that was more accurate and widely applicable than previously reported formulae. A total of 136 datasets from 75 patients were analyzed retrospectively. The median of free fraction of VPA was 0.16 (interquartile range: 0.07; range: 0.07-0.45). The parameter that combined total VPA concentration (CtVPA) and serum albumin (SA), (CtVPA [µM] - 2 × SA [µM]), was significantly related to the free fraction of VPA (r = 0.76, p < 0.001). We constructed a combined parameter-based prediction formula for unbound VPA concentration. Analysis using external datasets from patients without severe renal failure showed that the prediction errors of the unbound VPA concentration were lower than those of previously reported formulae. Although the previous formulae showed large prediction errors, especially in the specific range of CtVPA values, the constructed formula showed a weak trend with CtVPA or SA. The formula based on (CtVPA [µM] - 2 × SA [µM]) had high prediction accuracy and wide applicability in predicting the unbound VPA concentration in patients without severe renal failure.

Pharmacokinetics of vancomycin and meropenem during continuous online hemodiafiltration: A case report.

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.

Relationship between elevated bilirubin levels and enhanced warfarin effects during biliary obstruction.

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.

In vitro analysis of factors affecting the continuous hemodiafiltration clearance of teicoplanin.

BACKGROUND: In the treatment of sepsis, continuous hemodiafiltration (CHDF) and the administration of antibiotics such as teicoplanin (TEIC) are frequently performed in parallel. We aimed to clarify the factors influencing the CHDF clearance (CLCHDF ) of TEIC using a polymethylmethacrylate (PMMA) membrane or a polyacrylonitrile and sodium methallyl sulfonate copolymer membrane coated with polyethylenimine (AN69ST). We also investigated whether the adsorption of TEIC onto the hemofilters inhibits the adsorption of interleukin (IL)-6 onto the membranes. METHODS: TEIC, human serum albumin (HSA), and IL-6 were incubated with pieces of hemofilter membranes and adsorption rates were calculated. The CLCHDF , diafiltration rate, and adsorption rate of TEIC were calculated using an in vitro CHDF circuit model. RESULTS: The adsorption rates of TEIC onto the pieces of PMMA and AN69ST membranes ranged from 15.0% to 100% and from -10% to 5%, respectively. The adsorption rate of IL-6 was similar with or without TEIC. The CLCHDF and adsorption rate of TEIC under PMMA-CHDF depended on HSA, but not on effluent flow rate (Qe). The CLCHDF under AN69ST-CHDF depended on HSA and Qe. The observed CLCHDF under AN69ST-CHDF was similar to the predicted value (the product of Qe and the plasma unbound fraction). The observed CLCHDF under PMMA-CHDF was 2.0-7.8 times greater than the predicted value. CONCLUSIONS: Adsorption mainly contributes to the CLCHDF of TEIC using PMMA membranes, whereas diafiltration mainly contributes to the CLCHDF of TEIC using AN69ST membranes. TEIC adsorption might not affect the adsorption of IL-6 onto PMMA membrane.

Adverse effect investigation using application software after vaccination against SARS-CoV-2 for healthcare workers.

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®ï¸. METHODS: Healthcare workers (HCWs) who were vaccinated with Comirnaty®ï¸ 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.

Rosa centifolia petal extract induces endothelium-dependent and endothelium-independent vasorelaxation in rat aorta and prevents accumulation of inflammatory factors in human umbilical vein endothelial cells.

This study aims to investigate the vasorelaxation effects of a Rosa centifolia petal extract (ROSE CRYSTA®-70: ROSE-70) on the isolated aorta and the protective effect of ROSE-70 on human umbilical vein endothelial cells (HUVECs) dysfunction. ROSE-70 inhibited phenylephrine (PE) -induced contraction in an endothelium-dependent and endothelium-independent manner; however, this relaxation was lower in the endothelium-denuded aorta. ROSE-70-induced relaxation was attenuated by L-NG -nitroarginine methyl ester (L-NAME), a nitric oxide synthase inhibitor in the endothelium-intact aorta. Moreover, the relaxation in the endothelium-denuded aorta in response to increases in cAMP was inhibited by SQ22536, an adenylate cyclase inhibitor, and this relaxation was also attenuated by 4-aminopyridine, a voltage-activated K+ channel inhibitor. ROSE-70 contains high concentrations of quercetin, rutin, and other compounds. Pure quercetin and rutin also inhibited PE-induced contraction in an endothelium-dependent manner, although rutin-induced relaxation was milder in the endothelium-denuded aorta. ROSE-70 significantly increased the phosphorylation (at Ser1177) of eNOS in HUVECs. Moreover, ROSE-70 potently suppressed high glucose- and H2 O2 -induced accumulation of tumor necrosis factor-α (TNF-α) and nuclear factor-kappa B (NF-κB) were investigated in human umbilical vein endothelial cells (HUVECs). In this study, we defined the mechanism of ROSE-70-induced vasorelaxation in rat aorta and demonstrated that ROSE-70 has anti-inflammatory effects in endothelial cells. PRACTICAL APPLICATIONS: Endothelial cells play a role in vascular homeostasis. Endothelial dysfunction is caused by a variety of risk factors such as hypertension, arteriosclerosis, hyperglycemia, and oxidative stress. ROSE-70 is a food ingredient and the powdered form of an extract from the rose petal with >70% of the content corresponding to rose petal polyphenols such as rutin, quercetin, and protocatechuic acid. This study revealed that vasorelaxation effects of ROSE-70 and the protective role of ROSE-70 on the dysfunction of endothelial cells by high glucose and superoxides were investigated for the first time. We showed the mechanisms of ROSE-70- induced endothelium-dependent vasorelaxation and the protective effects of endothelial cells from high glucose and superoxide. ROSE-70 has been shown to have antiaging, skin elasticity-enhancing, skin-lightening, anti-allergic, sugar-absorbing, and lipolytic effects (URL: https://www.toyohakko-healthcare. com/en/rose_crysta70/). Therefore, the authors believe that ROSE-70 is an excellent food ingredient that has preventive and antiaging effects on lifestyle-related diseases.

Decrease of voriconazole trough levels during therapy with enteral nutrition: a case report.

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.

Analysis of the variable factors affecting changes in the blood concentration of cyclosporine before and after transfusion of red blood cell concentrate.

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.

Contribution of diafiltration and adsorption to vancomycin clearance in a continuous hemodiafiltration circuit model in vitro.

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.

Identification of factors affecting meropenem pharmacokinetics in critically ill patients: Impact of inflammation on clearance.

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.

Evaluation of association between parameters related to penetration into cerebrospinal fluid and the microbiological efficacy of vancomycin in patients with bacterial meningitis.

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.

Pharmacokinetically guided, once-daily intravenous busulfan in combination with fludarabine for elderly AML/MDS patients as a conditioning regimen for allogeneic stem cell transplantation.

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.

Transition of maternal serum concentration of digoxin and flecainide in the third trimester-A case report of fetal supraventricular tachycardia with hydrops.

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.

Suspected cholestatic liver injury induced by favipiravir in a patient with COVID-19.

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 ß-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.

Antibiotics prescriptions for pneumonia analyzed by claim information in Japan.

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.

Antibiotics for hospitalized children with community-acquired pneumonia in Japan: Analysis based on Japanese national database.

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 ß-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 ß-lactam and non-ß-lactam covering atypical bacteria. Ampicillin-sulbactam was the most frequently prescribed ß-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.

Evaluation of tacrolimus and mycophenolic acid removal by simultaneous continuous hemodiafiltration and plasma exchange in a lung transplant patient.

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.

A retrospective observational study of antibiotics treatment for sepsis using a nationwide claim database in Japan.

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.

Successful treatment of Aspergillus empyema using combined intrathoracic and intravenous administration of voriconazole: A case report.

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.

Effects of red blood cell concentrate transfusion on blood tacrolimus concentration.

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.