Identification of Patients Who Require Two-Point Blood Sampling for the Peak and Trough Values Rather Than One-Point Blood Sampling for the Trough Value for the Evaluation of AUC of Vancomycin Using Bayesian Estimation.

OBJECTIVES: It is recommended to adjust the dose of vancomycin (VCM) with a target area under the concentration-time curve (AUC) of 400-600 µg·h/mL. Factors that affect the deviation between AUCs are estimated from the trough value alone and the trough and peak values using practical AUC-guided therapeutic drug monitoring (PAT) for vancomycin. In this study, factors that affect AUC were evaluated. METHODS: AUCs were estimated from a single trough value and trough and peak values, and the patients were classified into those who showed a 10% or greater deviation (deviation group) and those in whom the deviation was less than 10% (no-deviation group). Risk factors related to ≥ 10% deviation of AUC were identified by univariate and multivariate analysis. RESULTS: As a result of univariate and multivariate analysis of 30 patients in the deviation group and 344 patients in the no-deviation group, a creatinine clearance (CLcr) of ≥ 110 mL/min (odds ratio (OR) = 3.697, 95% confidence interval (CI) = 1.616-8.457, p = 0.002), heart failure with a brain natriuretic peptide (BNP) of ≥ 300 pg/mL (OR = 4.854, 95%CI = 1.199-19.656, p = 0.027), and the concomitant use of angiotensin converting enzyme inhibitor or angiotensin II receptor blocker (ACE-I/ARB) (OR = 2.544, 95%CI = 1.074-6.024, p = 0.034) were identified as risk factors of ≥ 10% deviation of AUC. CONCLUSIONS: Estimation of AUC by two-point blood sampling for the trough and peak values rather than one-point blood sampling for the trough value is suggested to improve the prediction accuracy in patients with enhanced renal function, severe heart failure, and patients using ACE-I/ARB.

Flowchart for predicting achieving the target area under the concentration-time curve of vancomycin in critically ill Japanese patients: A multicenter retrospective study.

INTRODUCTION: In therapeutic drug monitoring (TDM) of vancomycin (VCM), the area under the concentration-time curve (AUC) is related to the clinical efficacy and toxicity. Therefore, herein, we examined the factors associated with achieving the target AUC at follow-up and developed a decision flowchart for achieving the target AUC in critically ill patients. METHODS: This multicenter retrospective observational study was conducted at eight hospitals. We retrospectively analyzed data from patients who had received VCM in the intensive care unit from January 2020 to December 2022. Decision-tree (DT) analysis was performed using factors with p < 0.1 in univariate analysis as the independent variables. Case data were split up to two times, and four subgroups were included. The primary endpoint was achieving the target AUC at the follow-up TDM (AUCfollow-up) and target AUCfollow-up achievement was defined as an AUC of 400-600 µg‧h/mL. The initial AUC values were calculated with the 2-point concentrations (peak and trough) using the Bayesian estimation software Practical AUC-guided TDM (PAT). RESULTS: Among 70 patients (median age [interquartile range], 66 [56, 79] years; 50 % women), the AUCfollow-up was achieved in 70 % (49/70). Three factors were selected for the decision flow chart: predicted AUCfollow-up of 400-600 µg‧h/mL, dosing at 12-h intervals, and CCr of 130 mL/min/1.73 m2 or higher; the accuracy was adequate (92 %, R2 0.52). CONCLUSION: We successfully identified the factors associated with achieving the target AUC of VCM at follow-up TDM and developed a simple-to-use DT model. However, the validity of the findings needs to be evaluated.

Risk Factors for Non-Adherence to Pharmacist or Non-Pharmacist Explanations on Preoperative Medication Discontinuation: A Retrospective Japanese Study.

Purpose: The risk factors for non-adherence to pharmacist or non-pharmacist explanations of preoperative medication discontinuation are unknown. The primary outcome of this study was to determine whether the final explainer's occupation was a risk factor for non-adherence. The secondary outcomes were to determine the risk factors for non-adherence after limiting the departments or adjusting for age. Patients and Methods: We retrospectively examined the data (including patient age, sex, prescription medications, comorbidities, presence of roommate, and number of days between receiving explanation and surgery) of 1132 patients on medications that could affect surgery at a Japanese university hospital between April 1, 2017, and March 31, 2020. The primary endpoint was whether the occupation of the last person explaining medication discontinuation to the patient was an independent risk factor for non-adherence (age ≥65 years vs <65 years). Secondary endpoints included subgroup analyses in urological, gastrointestinal, and otolaryngological areas, as well as a sensitivity analysis (age as a continuous variable) to confirm the validity of the primary endpoint results. A multivariate binary logistic regression identified independent non-adherence risk factors. Results: The main analysis showed that discontinuing two or more medications was a risk factor for non-adherence (adjusted odds ratio (AOR): 1.67; 95% confidence interval (CI): 1.13-2.47; p = 0.01). However, in analyses coordinated by department (urological, gastrointestinal, and otolaryngological), ≥65 (versus <65) years of age was determined as a risk factor for increased nonadherence (AOR: 2.27, 95% CI: 1.11-4.63; p=0.024). Age-adjusted analysis (continuous variables) showed similar results to the primary endpoint (AOR: 1.68, 95% CI: 1.14-2.49, p = 0.009). Conclusion: Two or more medications, and not the final explainer's occupation, were associated with pre-surgery medication non-adherence. To prevent non-adherence, pharmacists and non-pharmacists should educate patients about preoperative medication discontinuation. These findings could help identify high-risk non-adherence patients.

Relationship between nephrotoxicity and area under the concentration-time curve of vancomycin in critically ill patients: a multicenter retrospective study.

We aimed to assess the frequency of acute kidney injury (AKI) in different areas under the concentration-time curve (AUC) values of vancomycin (VAN) using a two-point blood collection method, allowing for accurate AUC assessment in critically ill patients. This multicenter retrospective observational study was conducted in eight hospitals. We retrospectively analyzed the data of patients who had received VAN in an intensive care unit (ICU) between January 2020 and December 2022. The primary outcome was the incidence of AKI. Patients were classified into three groups according to the AUC24-48h at the initial therapeutic drug monitoring (TDM) as follows: <500, 500-600, and ≥600 µg·h/mL. The AUC24-48h values were calculated using the Bayesian estimation software Practical AUC-guided TDM. Among 146 patients [median age (interquartile range), 67 (56-78) years; 39% women], the AUC24-48h <500 µg·h/mL had an AKI rate of 6.5% (7/107), the AUC24-48h 500-600 µg·h/mL had an AKI rate of 28.0% (7/25), and the AUC24-48h ≥600 µg·h/mL had an AKI rate of 42.9% (6/14). In multivariate Cox proportional hazard analysis, the AUC24-48h 500-600 µg·h/mL [hazard ratio 5.4, 95% confidence interval (CI) 1.64-17.63] and the AUC24-48h ≥600 µg·h/mL (hazard ratio 7.0, 95% CI 2.31-21.18) significantly correlated with a higher incidence of AKI compared with the AUC24-48h <500 µg·h/mL. In conclusion, we identified an association between AUC on day 2 and the risk of AKI in ICU patients, suggesting that not only AUCs above 600 µg·h/mL but also those between 500 and 600 µg·h/mL pose a risk for AKI. IMPORTANCE: Vancomycin (VAN) is a glycopeptide antibiotic and one of the most commonly used antibiotics for severe infections caused by methicillin-resistant Staphylococcus aureus. However, higher VAN concentrations have been associated with an increased risk of acute kidney injury (AKI). Herein, we aimed to assess the frequency of AKI in different areas under the concentration-time curve (AUC) values of VAN using a two-point blood collection method, allowing for accurate AUC assessment in critically ill patients. We identified an association between AUC on day 2 and the risk of AKI in intensive care unit patients, suggesting that not only AUCs above 600 µg·h/mL but also those between 500 and 600 µg·h/mL pose a risk for AKI. Therefore, individualized dosing is feasible, with pharmacists being able to optimize VAN doses to attain appropriate targets.

Tissue concentrations of antibiotics given prophylactically during colorectal cancer surgery.

BACKGROUND/AIMS: This study was designed to clarify the pharmacokinetics of prophylactically administered cefmetazole in serum, intestinal tissue, and subcutaneous adipose tissue in patients who underwent surgery for colorectal cancer. METHODOLOGY: Cefmetazole sodium (1 g) was given intravenously during the induction of anesthesia, followed by a 1-g dose after 3 hours. Blood samples were taken at the start of surgery, immediately before administration of the additional dose of cefmetazole, at the time of lesion resection, and at the time of wound closure. Tissue samples were obtained immediately after lesion resection and at the time of wound closure. Concentrations of cefmetazole in serum and tissue were measured by high performance liquid chromatography using an internal standard for calibration. Minimum inhibitory concentrations (MIC80) of cefmetazole for Escherichia coli, Klebsiella pneumoniae, and Bacteroides fragilis were measured, and pharmacokinetics were evaluated. RESULTS: In subcutaneous adipose tissue, cefmetazole concentrations were maintained higher than the MIC80's for E. coli and K. pneumoniae, but were low in all patients regardless of the time of measurement. CONCLUSIONS: The low transition rate of cefmetazole into subcutaneous adipose tissue indicates the need for additional measures, such as high-pressure washing of the subcutaneous wound tissue.

Efficacy of the bleeding risk scoring system for optimal prophylactic anticoagulation therapy of venous thromboembolism in trauma patients: a single-center, retrospective, observational cohort study.

BACKGROUND: We developed a bleeding risk scoring system (BRSS) using prophylactic anticoagulation therapy to comprehensively assess the risk of venous thromboembolism (VTE) in trauma patients. This study evaluated the usefulness of this system in trauma patients, with a focus on minimizing the rate of bleeding events associated with prophylactic anticoagulation therapy. METHODS: We retrospectively evaluated the efficacy of BRSS in trauma patients who received prophylactic anticoagulation therapy for VTE at the Kitasato University Hospital Emergency and Critical Care Center between April 1, 2015, and August 31, 2020. To compare the incidence of bleeding events, patients were divided into two groups: one group using the BRSS (BRSS group) and another group not using the BRSS (non-BRSS group). RESULTS: A total of 94 patients were enrolled in this study, with 70 and 24 patients assigned to the non-BRSS and BRSS groups, respectively. The major bleeding event rates were not significantly different between the two groups (BRSS group, 4.2%; non-BRSS group, 5.7%; p = 1.000). However, minor bleeding events were significantly reduced in the BRSS group (4.2% vs.27.1%; p = 0.020). Multivariate logistic regression analysis showed that BRSS was not an independent influencing factor of major bleeding events (odds ratio, 0.660; 95% confidence interval: 0.067-6.47; p = 0.721). Multivariate logistic regression analysis showed that BRSS was an independent influencing factor of minor bleeding events (odds ratio, 0.119; 95% confidence interval: 0.015-0.97; p = 0.047). The incidence of VTE did not differ significantly between groups (BRSS group, 4.2%; non-BRSS group, 8.6%; p = 0.674). CONCLUSIONS: BRSS may be a useful tool for reducing the incidence of minor bleeding events during the initial prophylactic anticoagulation therapy in trauma patients. There are several limitations of this study that need to be addressed in future research.

Venous thromboembolism risk factors and usefulness of a risk scoring system in lower limb orthopedic surgery: A case-control study in Japan.

ABSTRACT: We previously developed a computerized clinical decision support system based on national consensus guidelines and previous studies. This system was used to assess the risk of venous thromboembolism. In this study, we examined the risk factors for venous thromboembolism in patients who underwent lower limb orthopedic surgery using our risk scoring system, to investigate the association between the total risk score and the occurrence of venous thromboembolism.We retrospectively evaluated the records of 649 patients who underwent lower limb orthopedic surgery at a tertiary care center in Japan between January 2015 and August 2018. Venous thromboembolism was confirmed using ultrasonography or computed tomography angiography. The computerized clinical decision support system was used throughout the hospitalization period. Independent risk factors for postoperative venous thromboembolism were identified using logistic regression analysis.Age (≥68 years) was significantly associated with an increased risk of venous thromboembolism (adjusted odds ratio: 1.06, 95% confidence interval: 1.03-1.09; P < 0.001). Furthermore, the Cochran-Armitage trend test revealed a significant positive correlation between the total risk score and the occurrence of venous thromboembolism (P < 0.001).Our risk scoring system may be used preoperatively to determine the need for venous thromboembolism prophylaxis. This study suggests that age (≥68 years) may be a risk factor for venous thromboembolism after lower limb orthopedic surgery. Additional studies are needed to validate these results.

Risk Factors for Non-Adherence to Medications That Affect Surgery: A Retrospective Study in Japan.

Purpose: Data on risk factors for non-adherence to doctors' and pharmacists' instructions to discontinue medications prior to surgery are lacking. This study aimed to identify characteristics and risk factors for such non-adherent patients. Patients and Methods: Data (including patient age, sex, prescription medications, comorbidities, presence of roommate at home, and number of days between receiving instruction and surgery) of 887 patients who used medications affecting surgery at a university hospital from April 2017 to March 2020 were retrospectively evaluated. The primary endpoint was to investigate the rate of non-adherence and to explore independent risk factors for non-adherence (with age categorized as ≥65 [versus <65] years). Secondary endpoints included analysis of limited number of departments subgroup and a sensitivity analysis (with age categorized as ≥75 [versus <75] years) to confirm the robustness of the primary endpoint results. Independent risk factors for non-adherence were identified using logistic regression analysis. Results: The non-adherence rate was 11.4% (n=101/887), median age (interquartile range) at admission was 73 (70-79) years, and proportion of male patients was 81.2% (n=82). The main analysis adjusted for age ≥65 (versus <65) years showed age as a risk factor for increased non-adherence (adjusted odds ratio: 2.1, 95% confidence interval: 1.09-4.05; p=0.027). However, analyses adjusted for departments (other than urology, gynecology, and breast surgery, with a large sex bias in hospitalized patients) and for age ≥75 (versus <75) years showed no such risk. Conclusion: Age ≥65 years was associated with a higher risk of non-adherence to medications that should be discontinued before surgery. It is important for doctors and pharmacists to ensure that patients at high risk for non-adherence are aware of the importance of adherence. Our findings may help identify patients at high risk for non-adherence to such medications.

Internal Validation of a Risk Scoring System for Venous Thromboembolism After Total hip or Knee Arthroplasty.

We developed a computerized clinical decision support system (CCDSS) for venous thromboembolism (VTE) risk assessment. We aimed to demonstrate its relevance and evaluate associations between risk level and VTE incidence in patients undergoing total hip/knee arthroplasty. In this case-control study, VTE was confirmed using ultrasonography/computed tomography angiography in 1098 adults at a tertiary care hospital over five years (2013-2018). Postoperative VTE incidence was classified into three risk levels (moderate, high, and highest). The overall VTE incidence was 11.7%, which increased with a risk level of 0%, 5.8%, and 12.8% in moderate-risk, high-risk, and highest-risk patients, respectively. Highest-risk patients were significantly more likely to develop VTE than high-risk patients (odds ratio [OR] 2.4; 95% confidence interval [CI] 1.2-5.5; p = 0.01). VTE development was more likely in patients with risk scores ≥4 relative to those with risk scores of 2-3 (OR 1.8; 95% CI 1.2-2.7; p = 0.003) and -1 to 1 (OR 3.3; 95% CI 1.6-7.7; p < 0.001). This study indicates that risk level and VTE incidence are associated; our scoring system appears useful for patients undergoing total hip/knee arthroplasty.

Efficient Degradation of Poly(ethylene terephthalate) with Thermobifida fusca Cutinase Exhibiting Improved Catalytic Activity Generated using Mutagenesis and Additive-based Approaches.

Cutinases are promising agents for poly(ethylene terephthalate) (PET) bio-recycling because of their ability to produce the PET monomer terephthalic acid with high efficiency under mild reaction conditions. In this study, we found that the low-crystallinity PET (lcPET) hydrolysis activity of thermostable cutinase from Thermobifida fusca (TfCut2), was increased by the addition of cationic surfactant that attracts enzymes near the lcPET film surface via electrostatic interactions. This approach was applicable to the mutant TfCut2 G62A/F209A, which was designed based on a sequence comparison with PETase from Ideonella sakaiensis. As a result, the degradation rate of the mutant in the presence of cationic surfactant increased to 31 ± 0.1 nmol min-1 cm-2, 12.7 times higher than that of wild-type TfCut2 in the absence of surfactant. The long-duration reaction showed that lcPET film (200 µm) was 97 ± 1.8% within 30 h, the fastest biodegradation rate of lcPET film thus far. We therefore believe that our approach would expand the possibility of enzyme utilization in industrial PET biodegradation.

Optimal dosage of cefmetazole for intraoperative antimicrobial prophylaxis in patients undergoing surgery for colorectal cancer.

BACKGROUND: Few studies have reported the dosage of cefmetazole (CMZ) for intraoperative antimicrobial prophylaxis in patients underwent surgery for colorectal cancer. We therefore examined the optimal intraoperative dosage of CMZ according to pharmacokinetic/pharmacodynamic (PK/PD) theory in patients who undergoing surgery for colorectal cancer. METHODS: The study group comprised 23 patients with colorectal cancer who underwent surgery, using CMZ as antimicrobial treatment to prevent postoperative infection. CMZ was administered intravenously within 60 min before surgery. PK/PD analysis was performed by population pharmacokinetic analysis and Monte-Carlo simulation. RESULTS: The final population pharmacokinetic parameters of CMZ were as follows: CLCMZ = 0.0704 × creatinine clearance (Ccr) and VdCMZ = 0.163 × body weight (Bw). In patients with a Ccr of ≥90 to <130 mL/min, the probability of achieving concentrations exceeding MIC was 52.9 to 82.2% at 2 h after the initial dose and less than 20% at 3 h after the initial dose. CONCLUSIONS: Additional doses of CMZ should be given every 2 h in patients with a Ccr of ≥90 to <130 mL/min, every 3 h in those with a Ccr of ≥50 to <90 mL/min, and every 4 to 5 h in those with a Ccr of ≥10 to <50 mL/min.