Using Japanese big data to investigate novel factors and their high-risk combinations that affect vancomycin-induced nephrotoxicity.

AIMS: Several factors related to vancomycin-induced nephrotoxicity (VIN) have not yet been clarified. In the present study, we used Japanese big data to investigate novel factors and their high-risk combinations that influence VIN. METHODS: We employed a large Japanese electronic medical record database and included patients who had been administered intravenous vancomycin between June 2000 and December 2020. VIN was defined as an increase in serum creatinine ≥0.5 mg/dL or 1.5-fold higher than the baseline. The outcomes were: (1) factors affecting VIN that were identified using multiple logistic regression analysis, and (2) combinations of factors that affect the risk of VIN according to a decision tree analysis, which is a typical machine learning method. RESULTS: Of the 7306 patients that were enrolled, VIN occurred in 14.2% of them (1035). A multivariate analysis extracted 22 variables as independent factors. Concomitant ramelteon use (odds ratio 0.701, 95% confidence interval 0.512-0.959), ward pharmacy service (0.741, 0.638-0.861), duration of VCM < 7 days (0.748, 0.623-0.899) and trough concentrations 10-15 mg/L (0.668, 0.556-0.802) reduce the risk of VIN. Meanwhile, concomitant piperacillin-tazobactam use (2.056, 1.754-2.409) and piperacillin use (2.868, 1.298-6.338) increase the risk. The decision tree analysis showed that a combination of vancomycin trough concentrations ≥20 mg/L and concomitant piperacillin-tazobactam use was associated with the highest risk. CONCLUSIONS: We revealed that the concomitant ramelteon use and ward pharmacy service may decrease the risk of VIN, while the concomitant use of not only piperacillin-tazobactam but also piperacillin may increase the risk.

Effects of piperacillin/tazobactam or cefepime on folinate dose in patients receiving high-dose methotrexate: A retrospective cohort study using Japanese administrative claims data.

INTRODUCTION: Delayed methotrexate (MTX) clearance with the co-administration of piperacillin/tazobactam (PIPC/TAZ) has been reported. Penicillins have been associated with reduced MTX clearance but the evidence is limited. There are no cases described with cefepime but penicillins are listed as interacting with MTX. We aimed to reveal whether the co-administration of PIPC/TAZ or CFPM affects MTX clearance using data from an administrative database. METHODS: We used data from the JMDC database, a large insurance claims database constructed in Japan. We included patients who were prescribed PIPC/TAZ or CFPM between days 1 and 3 in high-dose MTX (HD-MTX). We compared one co-administration episode (with PIPC/TAZ or CFPM) to one control episode (without), as a match-control study of two different episodes in the same patient. The primary outcomes were the duration and cumulative dose of leucovorin (LV) as a surrogate indicator of delayed MTX clearance. RESULTS: Three patients who were co-administered PIPC/TAZ and 16 patients who were co-administered CFPM with HD-MTX were included. In the PIPC/TAZ group, the duration and the cumulative doses of LV were similar in co-administration and control episode (median 3.0 vs. 3.0 days and 288.0 vs. 219.0 mg). In the CFPM group, the duration and the cumulative doses of LV were not significantly different in co-administration and control episode (3.0 vs. 4.0 days and 169.5 vs. 258.0 mg). CONCLUSIONS: Our findings revealed that PIPC/TAZ did not necessarily cause a delay in MTX clearance during HD-MTX therapy. Moreover, the co-administration of CFPM with HD-MTX did not affect MTX clearance.

Comparison of interactions between warfarin and cephalosporins with and without the N-methyl-thio-tetrazole side chain.

Cephalosporins with an N-methyl-thio-tetrazole (NMTT) side chain interact with warfarin by reducing the production of blood clotting factors. However, cephalosporins without the NMTT side chain also enhance the effects of warfarin. Thus, we aimed to compare the effects of warfarin modified by cephalosporins with and without the NMTT side chain, using a Japanese health insurance claims database. The inclusion criteria were patients who (1) intravenously received second- or third-generation cephalosporins between April 2010 and March 2017 and (2) received warfarin during cephalosporin therapy. Patients were administered either cephalosporins with the NMTT side chain (NMTT group) or those without NMTT (non-NMTT group). After matching patient data by propensity score, the following outcomes were compared between the two groups: (1) proportion of patients administered vitamin K, (2) proportion of bleeding events, and (3) changes in the daily dose of warfarin. Among 203 patients, 100 patients (50 per group) were matched by the propensity score. The proportion of patients administered vitamin K was 6.0% in both groups. These patients intravenously received a single dose of menatetrenone; no bleeding was observed. The proportion of patients subjected to a reduction in the daily dose of warfarin was 6.5% and 4.3% in the NMTT and non-NMTT groups, respectively. As our study had a small sample size, we could not determine whether the risk of over anticoagulation of warfarin is affected by cephalosporins with or without NMTT side chain. However, we showed the bleeding risk was sufficiently low regardless of the presence/absence of the NMTT side chain.

[Therapeutic Drug Monitoring of Antimicrobial Agents].

Antimicrobial dosing can be targeted to achieve pharmacokinetic (PK) -pharmacodynamic parameters at the minimal inhibitory concentration of bacteria. Therapeutic drug monitoring (TDM) of glycopetides [vanco- mycin (VCM) and teicoplanin] and aminoglycosides (gentamicin, tobramycin, and amikacin) makes it possible to optimize dosing in individual patients. TDM of these antimicrobials can improve clinical outcomes, de- crease adverse events, and reduce costs. Therefore, PK-monitoring for VCM and aminoglycosides is rec- ommended in the Antimicrobial Stewardship Program implementing guidelines developed by the Infectious Disease Society of America and the Society for Healthcare Epidemiology of America in 2016. In addition, Clinical practice guidelines for TDM have been developed by the Japanese Society of Chemotherapy and the Japanese Society of TDM since 2012, and they were updated in 2016. The aim of this study was to review TDM of antimicrobial agents. [Review].

[Factors Resulting Correlation and Differences in Renal Function Evaluation Index Using the Serum Cystatin C and Creatinine as Measured by an Enzymatic Method].

We previously reported the association of the estimated glomerular filtration rate (eGFRcreat) calculated from the serum creatinine level (S-Cr) measured using the Jaffe method with the GFR (eGFRcys) estimated from the serum cystatin C level (CysC). However, few studies have compared the eGFRcreat using the enzymatic method with the eGFRcys. It is unclear whether there are differences in the results of renal function assessment. The purpose of this study was to compare the eGFRcreat calculated from the S-Cr with the eGFRcys calculated from the CysC in patients in whom the S-Cr and CysC were simultaneously measured using the enzymatic method, examine the correlations of respective parameters, and clarify physiological factors involved in differences among the parameters. The subjects were 1334 patients treated in 5 institutions. The mean values and correlation coefficient were statistically analyzed using Student's t-test and Pearson's test, respectively. Influential factors between formulae were analyzed using multiple regression analysis. The mean eGFRcreat was 67.0 mL/min/1.73 m2, being significantly higher than the mean eGFRcys (63.2). Multiple regression analysis showed that factors influencing differences in the S-Cr and CysC included the sex, age, serum albumin, and blood urea nitrogen BUN/S-Cr. Furthermore, factors involved in the overestimation of the eGFRcreat in comparison with the eGFRcys included the serum albumin and BUN/S-Cr. The differences between the eGFRcreat calculated from the S-Cr and eGFRcys were less marked than when adopting the Jaffe method in our previous study. However, the eGFRcreat were higher than the eGFRcys in patients with malnutrition or dehydration.

A Risk Prediction Flowchart of Vancomycin-Induced Acute Kidney Injury to Use When Starting Vancomycin Administration: A Multicenter Retrospective Study.

We previously constructed a risk prediction model of vancomycin (VCM)-associated nephrotoxicity for use when performing initial therapeutic drug monitoring (TDM), using decision tree analysis. However, we could not build a model to be used at the time of initial administration due to insufficient sample size. Therefore, we performed a multicenter study at four hospitals in Japan. We investigated patients who received VCM intravenously at a standard dose from the first day until the initial TDM from November 2011 to March 2019. Acute kidney injury (AKI) was defined according to the criteria established by the "Kidney disease: Improving global outcomes" group. We extracted potential risk factors that could be evaluated on the day of initial administration and constructed a flowchart using a chi-squared automatic interaction detection algorithm. Among 843 patients, 115 (13.6%) developed AKI. The flowchart comprised three splitting variables (concomitant drugs (vasopressor drugs and tazobactam/piperacillin) and body mass index ≥ 30) and four subgroups. The incidence rates of AKI ranged from 9.34 to 36.8%, and they were classified as low-, intermediate-, and high-risk groups. The accuracy of flowchart was judged appropriate (86.4%). We successfully constructed a simple flowchart predicting VCM-induced AKI to be used when starting VCM administration.

Higher incidence of acute kidney injury in patients treated with piperacillin/tazobactam than in patients treated with cefepime: a single-center retrospective cohort study.

BACKGROUND: Piperacillin/tazobactam (PIPC/TAZ) and cefepime (CFPM) are commonly used for the treatment of nosocomial and healthcare-associated infections. Recent reports have suggested that the incidence of acute kidney injury (AKI) in patients treated with a combination of vancomycin (VCM) and PIPC/TAZ is higher than that in patients treated with CFPM. However, there have been few reports on a comparison of the incidences of AKI in patients treated with PIPC/TAZ monotherapy and patients treated with CFPM. In this study, we investigated whether the incidence of AKI in patients treated with PIPC/TAZ is higher than that in patients treated with CFPM. METHODS: This study was a single-center retrospective observational study. Patients who died during the therapeutic period, patients younger than 18 years of age, and patients undergoing hemodialysis were excluded. Primary outcomes were the incidence of AKI and the AKIN stages defined by the Acute Kidney Injury Network. Secondary outcomes were discontinuation and/or change of antibiotics and initiation of dialysis due to AKI. We also investigated the time to onset and the risk factors of AKI in this population. RESULTS: There were 163 patients in the PIPC/TAZ group and 103 patients in the CFPM group. The incidence of AKI in patients treated with PIPC/TAZ (8.6%) was significantly higher than that in patients treated with CFPM (0.9%) (odds ratio (OR), 9.53; 95% confidence interval (CI), 1.41-408; p= 0.011). AKI severity was mostly stage 1 in both groups. There was no discontinuation and/or changes of antibiotics and there was no initiation of dialysis in either group. The onset of AKI in the PIPC/TAZ group (median period of 4 days) was earlier than that in the CFPM group. PIPC/TAZ was determined to be an independent risk factor of AKI in multivariate analysis (adjusted OR, 9.56; 95% CI, 1.21-75.3; p = 0.032). CONCLUSIONS: This study showed that the incidence of AKI in patients who received PIPC/TAZ was higher than that in patients who received CFPM. Furthermore, the onset of AKI was earlier in patients who received PIPC/TAZ than in patients who received CFPM. PIPC/TAZ was an independent risk factor of AKI in this study population.

The use of an in vitro dissolution and absorption system to evaluate oral absorption of two weak bases in pH-independent controlled-release formulations.

The aim of this study was to compare the oral absorption of two weak bases including their pH-independent controlled-release preparations using an in vitro evaluation system. This system is able to simulate dissolution of drugs, pH change and permeation of drugs through the epithelial cell membrane in the gastrointestinal tract. Albendazole-polymers solid dispersion and pH-independent sustained-release granules of dipyridamole were prepared by using a solvent method. Elution profiles and predicted absorption of these preparations in gastric pH conditions similar to those in healthy subjects and patients with achlorhydria were compared with those of a physical mixture and commercial tablets. When a physical mixture or commercial tablets were used, the elution profile and predicted absorption of both albendazole and dipyridamole were extremely pH-dependent. On the other hand, when a solid dispersion and granules were used, elution and predicted absorption were not affected by changes in pH of the flowing solution in a drug-dissolving vessel. These results are in agreement with the results of our previous in vivo study using gastric acidity-controlled rabbits. Our results suggest that this in vitro system is useful for the evaluation of oral absorption of pH-independent controlled-release preparations.

A new system for the prediction of drug absorption using a pH-controlled Caco-2 model: evaluation of pH-dependent soluble drug absorption and pH-related changes in absorption.

One purpose of this study was to develop a new system for the prediction of pH-dependent soluble drug absorption that takes into account the physiological condition of the gastrointestinal tract. Another purpose was to establish several models of different gastric acidities: a normal gastric acidity model, a low gastric acidity model (a model of achlorhydria), a temporarily elevated gastric acidity model (a model of a case in which an acidic drug was coadministered to temporarily elevate gastric acidity in the case of low gastric acidity), a weak antacid model (a model of a case in which a weak antacid drug, such as an H(2) receptor antagonist, was coadministered to temporarily elevate pH up to 6), and a strong antacid model (a model of a case in which a strong antacid drug, such as magnesium hydroxide, was coadministered to temporarily elevate pH up to 8.0). These models were used to evaluate variation in pH-related absorption in humans. Dipyridamole preparation (Persantin tablets) and glibenclamide preparation (Euglucon tablets), both poorly water-soluble and pH-dependent soluble drugs, were chosen as model drugs to determine whether absorption is altered by changes in levels of gastric acid. The extent of absorption of dipyridamole was remarkably lower when gastric pH was continuously elevated to 6.0, whereas it was increased when gastric pH temporarily decreased to 1.8. The extent of absorption of glibenclamide increased dramatically when gastric pH temporarily increased to 8.0, but did not change when gastric pH temporarily increased to 6.0. These results are consistent with reported results obtained in clinical studies. The results suggest that pH-related variations in absorption in humans can be accurately predicted using our new system.