論文 - 松元　一明

Development and external validation of a population pharmacokinetic model and optimal Vancomycin dosing regimen for overweight and obese patients

Komatsu T., Tomizawa A., Samura M., Suzuki A., Ishigo T., Fujii S., Ibe Y., Yoshida H., Tanaka H., Fujihara H., Yamaguchi F., Ebihara F., Maruyama T., Yagi Y., Hamada Y., Nagumo F., Takuma A., Chiba H., Nishi Y., Igarashi Y., Enoki Y., Otori K., Matsumoto K.

Journal of Infection and Chemotherapy 31 （ 12 ） 102838 2025年12月

共著,  ISSN  1341321X

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Introduction: This study aimed to develop and evaluate a population pharmacokinetic model and optimal dosing regimen for vancomycin in overweight and obese adults. Methods: A population pharmacokinetic model using a two-compartment system was constructed using a nonlinear mixed-effects approach, incorporating 527 data points from 184 participants. External validation of the model was carried out using an additional 55 data points from 21 participants; these were not used in the construction of the model. Monte Carlo simulations were used to determine the dosage that achieved the steady state area under the curve value falling between 400 μg h/mL and 600 μg h/mL. Results: In the final model, vancomycin clearance was found to be a significant predictor of blood vancomycin levels, alongside creatinine clearance (CCr), blood urea nitrogen levels, and incidence of heart failure. CCr was calculated with adjusted body weight (AdjBW). AdjBW was selected as a predictor of the volume of distribution in the central and peripheral compartments. External validation showed that the highest proportion of cases had deviations of less than 15 % between measured and predicted values in the final model developed in this study. This indicates that our model outperforms previously developed models (five for obese patients and four for non-obese patients). Conclusions: Our model shows that determining effective vancomycin doses for overweight and obese patients depend on estimated CCr rates, AdjBW, BUN levels, and incidence of heart failure.

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Evaluating the Necessity of Two-Point Sampling for Vancomycin Area Under the Curve in Follow-up Therapeutic Drug Monitoring.

Suzuki A, Fujihara H, Yamaguchi F, Yoshida H, Tanaka H, Yagi Y, Maruyama T, Hamada Y, Ishigo T, Fujii S, Nagumo F, Samura M, Chiba H, Ebihara F, Takuma A, Komatsu T, Tomizawa A, Nishi Y, Igarashi Y, Enoki Y, Matsumoto K

Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy 31 （ 11 ） 102821 2025年09月

共著,  ISSN  1341-321X

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Objective: While both peak and trough (two-point) sampling are recommended to estimate the area under the concentration-time curve (AUC) for vancomycin, one-point sampling may reduce clinical burden. This study aimed to identify patient populations requiring two-point sampling by examining risk factors associated with AUC discrepancies between one- and two-point sampling during follow-up therapeutic drug monitoring (TDM). Method: This multicenter retrospective observational study included adult patients who received vancomycin from September 2020 to December 2023 and underwent two-point sampling at both initial and follow-up TDM. AUC was estimated using the Practical Antimicrobial TDM (PAT) version 4.0, and creatinine clearance (CLcr) was calculated using the Cockcroft-Gault equation. One- and two-point follow-up AUCs were compared using previously entered two-point concentrations from initial TDM. Patients were divided into a discrepancy group (AUC difference ≥10 %) and a non-discrepancy group. Risk factors were identified by univariate and multivariate analysis. Results: AUC values from one- and two-point sampling in 256 cases were highly correlated (r² = 0.965, p < 0.001). Seventeen cases (6.6 %) showed discrepancies ≥10 %. Multivariate analysis identified BMI ≥25 kg/m² (OR = 6.946, p = 0.001), CLcr <50 mL/min (OR = 5.863, p = 0.002), and ΔCLcr ≥10 mL/min (OR = 4.444, p = 0.012) as significant risk factors. Conclusion: Although one- and two-point AUCs showed strong correlation, discrepancies ≥10 % were more likely in patients with elevated BMI or impaired/unstable renal function. This suggests that two-point sampling may be essential for these patients to ensure accurate dosing of vancomycin during follow-up TDM.

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Efficacy and Safety of Isavuconazole for Invasive Fungal Infections: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Kawasaki A, Shintani R, Takao R, Nakazawa Y, Mihara T, Ikegami S, Shimada S, Matsumoto Y, Okamoto Y, Igarashi Y, Enoki Y, Taguchi K, Matsumoto K

Medical mycology 63 （ 10 ）  2025年09月

共著,  ISSN  1369-3786

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Background Isavuconazole (ISA) is a treatment option for invasive fungal infections (IFIs) and is known for a favorable safety profile compared with other antifungal agents. However, comprehensive evidence regarding its efficacy and safety remains limited. Objectives This study aimed to assess the efficacy and safety of ISA compared with other antifungal agents through a systematic review and meta-analysis restricted to randomized controlled trials (RCTs), to provide more reliable estimates of its clinical effects. Methods Following Preferred Reporting Items for Systematic reviews and Meta-Analysis (PRISMA) guidelines, a comprehensive literature search was conducted using PubMed, the Cochrane Library, Web of Science, and ClinicalTrials.gov to identify RCTs comparing ISA with other antifungal agents. The primary outcomes were clinical response and mortality. Secondary outcomes included the incidence of adverse events, including serious, drug-related, and organ-specific toxicities. A subgroup analysis was conducted focusing on filamentous fungal infections, comparing ISA and voriconazole. Results Three RCTs met the inclusion criteria. No statistically significant differences were observed between ISA and comparator agents in terms of clinical response, mortality, or total and organ-specific adverse events. A trend toward fewer adverse events was noted in the ISA group. In the subgroup analysis, ISA and voriconazole showed similar efficacy and overall safety; however, the incidence of both drug-related adverse events and hepatobiliary disorders was significantly lower in the ISA group. Conclusions ISA demonstrated efficacy comparable to that of other antifungal agents, with a favorable safety profile in patients with IFIs, including filamentous fungal infections. This meta-analysis of RCTs provides high-quality evidence to support antifungal drug selection in clinical practice.

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Oral β-lactam combinations are effective in vitro against Mycobacterium avium, regardless of clarithromycin susceptibility.

Yoshikawa M, Nishimura T, Misawa K, Shimamura R, Suzuki K, Kashimura S, Igarashi Y, Enoki Y, Taguchi K, Hasegawa N, Namkoong H, Matsumoto K

Microbiology spectrum 13 （ 11 ） e0201225 - 15 2025年09月

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The global incidence and prevalence of pulmonary disease caused by the Mycobacterium avium complex (MAC), mainly comprising M. avium and Mycobacterium intracellulare, is increasing. However, treating MAC pulmonary disease is challenging in cases of clarithromycin (CLR)-resistant MAC or where the patients experience adverse effects or drug interactions with the few available antibiotics. Therefore, developing novel and highly effective antibiotics against MAC is crucial. Although the efficacy of dual β-lactams against Mycobacterium abscessus has been receiving attention, the efficacy of dual β-lactams against MAC remains unclear. Here, we used MAC type strains and clinical isolates to determine whether dual β-lactams were effective against MAC and which combinations synergistically inhibited bacterial growth using a broth microdilution checkerboard assay with 6 oral and 22 intravenous antibiotics. The combination effect and antibacterial activity differed between M. avium and M. intracellulare. Five combinations of oral β-lactams and 78 combinations of intravenous β-lactams showed a synergistic effect against the M. avium type strain. Among the M. avium clinical isolates, faropenem combined with cefuroxime showed the highest synergistic effect, and amoxicillin combined with tebipenem showed the lowest minimum inhibitory concentration. There was no significant difference in the combination effects between the CLR-susceptible and CLR-resistant M. avium clinical isolates in these pairs. In conclusion, regardless of CLR susceptibility, the oral β-lactam combinations were effective against M. avium. Thus, when treating MAC pulmonary disease, it is crucial to determine whether M. avium or M. intracellulare is the cause. IMPORTANCE Mycobacterium avium complex causes chronic respiratory infections, but treatment is often limited by drug resistance, intolerance, or interactions. As new therapeutic strategies are urgently needed, we focused on β-lactam antibiotics, which are widely used and well tolerated. Although dual β-lactams are effective against Mycobacterium abscessus, their utility against Mycobacterium avium complex has remained largely unexplored. Our in vitro study revealed that several β-lactam combinations are effective against Mycobacterium avium, regardless of drug resistance, indicating potential for clinical use. In contrast, Mycobacterium intracellulare showed lower susceptibility to β-lactams. Given this difference in drug susceptibility, we emphasize the clinical need to distinguish Mycobacterium avium and Mycobacterium intracellulare to optimize treatment of Mycobacterium avium complex pulmonary disease.

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Development of vancomycin population pharmacokinetic models for pediatric patients using a real-world web application database.

Oda K, Shoji K, Matsumoto K, Kawamura H, Takesue Y, Shigemi A, Kimura T

Journal of the Pediatric Infectious Diseases Society 14 （ 10 ）  2025年09月

共著,  ISSN  2048-7193

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Background: The Japanese Society of Chemotherapy developed practical area under the concentration-time curve (AUC)-guided therapeutic drug monitoring (PAT), a freely available web-based application widely used in Japan to support AUC-guided dosing of vancomycin. Its broad adoption has generated a substantial real-world pharmacokinetic database. Although PAT includes a preliminary pediatric model based on data from American children aged 3 months or older, that model requires further optimization. This study aimed to develop a population pharmacokinetic (popPK) model specifically for Japanese pediatric patients and to compare its performance with existing models. Methods: We utilized a real-world database collected through PAT between December 2022 and October 2024, comprising 1673 pediatric patients aged 3 months or older. Population pharmacokinetic analysis was performed using nonlinear mixed-effects modeling, with comparisons made against 5 existing models. Results: The developed model demonstrated strong a priori predictive performance for empirical vancomycin dosing, with a mean prediction error of 0.2 μg/mL and a mean absolute prediction error of 5.6 μg/mL. These results showed no apparent bias. Graphical diagnostics confirmed optimal a priori prediction in the developed model. A posteriori predictive performance—used for Bayesian posterior dosing—was similarly favorable across all models. Notably, 2-point sampling produced significantly different clearance estimates compared with 1-point sampling in 21 of 116 patients (18.1%). Conclusions: For Japanese pediatric patients aged 3 months or older, the developed popPK model is suitable for both empirical and Bayesian-guided vancomycin dosing. Two-point sampling improves the accuracy of clearance estimation and is recommended when feasible.

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Prediction of treatment success in patients with Enterococcus faecium bacteremia using vancomycin AUC(24)/MIC ratio: A multicenter retrospective study.

Hanai Y, Matsumoto K, Hanawa K, Endo A, Hashi H, Miyazaki T, Yamaguchi T, Harada S, Yokoo T, Uekusa S, Yokoyama Y, Maruyama R, Tsujimura S, Asakawa D, Namiki T, Isoda R, Enoki Y, Taguchi K, Matsuo K

Diagnostic microbiology and infectious disease 113 （ 2 ） 116961 2025年06月

共著,  ISSN  0732-8893

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Background: Although vancomycin is commonly used to treat Enterococcus faecium infections, there are no clear guidelines for the optimal 24-h area under the concentration time curve to minimum inhibitory concentration (AUC<inf>24</inf>/MIC) ratio. This study aimed to determine the target AUC<inf>24</inf>/MIC ratio associated with vancomycin-treated E. faecium infection outcomes. Methods: This retrospective multicenter cohort study included adult patients who received vancomycin for ≥5 days for E. faecium-associated bloodstream infections between January 2018 and December 2023. The primary outcome was treatment success, defined as a composite of survival beyond 30 days, clinical success, and microbiological eradication. Secondary outcomes included 30-day mortality, clinical success, microbiological eradication, and nephrotoxicity. Receiver operating characteristic (ROC) curve analysis identified the AUC<inf>24</inf>/MIC cut-off value for treatment success. Multivariate regression analysis was used to determine the association between AUC<inf>24</inf>/MIC and outcomes. Results: This study included 81 patients. ROC analysis identified AUC<inf>24</inf>/MIC ≥427 as the cutoff value for treatment success. The overall treatment success rate (71.6 %) was significantly higher in the above AUC<inf>24</inf>/MIC cut-off group (81.8 %) than in the below AUC<inf>24</inf>/MIC cut-off group (59.5 %). On multivariate analysis, AUC<inf>24</inf>/MIC ≥427 was an independent predictor (adjusted odds ratio: 4.399, 95 % confidence interval: 1.203–19.320, p = 0.024) of treatment success. The clinical success and microbiological eradication rates differed significantly between the below- and above-cut-off groups, whereas nephrotoxicity rates were comparable between the groups. Conclusions: In treating E. faecium infections, vancomycin AUC<inf>24</inf>/MIC ratio ≥427 was independently associated with treatment success. However, further prospective studies are required to confirm the AUC<inf>24</inf>/MIC target.

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Risk stratification of AUC upward deviation in patients with low serum creatinine levels treated with vancomycin: a multicenter retrospective study.

Ishigo T, Suzuki A, Ibe Y, Fujii S, Fukudo M, Yoshida H, Tanaka H, Fujihara H, Yamaguchi F, Ebihara F, Maruyama T, Hamada Y, Samura M, Nagumo F, Komatsu T, Tomizawa A, Takuma A, Chiba H, Nishi Y, Enoki Y, Taguchi K, Matsumoto K

The Journal of pharmacy and pharmacology 77 （ 9 ） 1255 - 1263 2025年06月

共著,  ISSN  0022-3573

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Introduction In patients with diminished muscle mass, serum creatinine (SCr) levels may be misleadingly low, potentially leading to overestimations of kidney function and unexpectedly high blood levels of vancomycin. This study aimed to identify factors contributing to this discrepancy and develop a flowchart for stratifying the risk of excessive vancomycin exposure, measured as an upward deviation in the area under the concentration-time curve (AUC) in patients with low SCr levels. Methods We analyzed data from patients who received vancomycin and had an SCr value <0.6 mg/dL. The discrepancy between the AUC<inf>24-48 h initial dosing</inf> and AUC<inf>24-48 h TDM</inf> was calculated; a ratio (AUC<inf>24-48 h TDM</inf>/AUC<inf>24-48 h initial dosing</inf>) higher than 1.2 defined an upward deviation in the AUC. A decision tree model was constructed using classification and regression tree algorithms. Results Among the 95 patients (median age [interquartile range], 69 [58, 80] years; 68% female), the upward AUC deviation was 40% (38/95). Three factors (creatinine clearance: 115 ml/min, age: 69 years, and blood urea nitrogen/SCr: 17) were selected for the decision flowchart and included in four subgroups. Conclusion We developed a flowchart to identify patients with low SCr levels whose AUC at therapeutic drug monitoring deviated upward by >20% from the predicted AUC.

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CKD-Induced Oxidative Twitch Muscle Atrophy is Mediated by Transforming Growth Factor-β.

Homma K, Enoki Y, Taguchi K, Matsumoto K

Kidney360 6 （ 9 ） 1438 - 1447 2025年06月

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Background: Understanding the vicious cycle driving renal impairment progression and skeletal muscle atrophy in chronic kidney disease (CKD) is crucial. Therefore, this study aimed to examine the role of transforming growth factor-beta (TGF-β) in promoting skeletal muscle atrophy in CKD. Methods: A combined model of 2/3 nephrectomy and unilateral ureteral ligation, as we previously reported, was used for CKD mice. Skeletal muscle weight and changes in skeletal muscle fiber twitch type were evaluated. Using C2C12 cells, a skeletal muscle myoblast cell line, molecules that induce a reduction in type IIa muscle fibers in CKD were identified. The identified molecule, TGF-β, was administered to mice to investigate its effects on muscle fiber-type changes. Furthermore, the effects of administering a TGF-β inhibitor to CKD mice were evaluated. Results: In CKD mice, myosin heavy chain (MyHC)-specific antibody immunostaining showed an increase in atrophied MyHC IIa (oxidative twitch) muscle fibers. CKD mouse serum preferentially induces MyHC IIa fiber atrophy in C2C12 cells. TGF-β-treated mice had reduced levels of oxidative metabolic skeletal muscle and oxidative type IIa fiber, similar to CKD mice. Furthermore, TGF-β inhibitor treatment prevented the CKD-associated decrease in oxidative type IIa muscle fiber size and reduced exercise capacity. Conclusions: These findings indicate that TGF-β causes skeletal muscle deterioration in CKD by reducing oxidative metabolism and inducing type IIa fiber atrophy. In addition, our results emphasize that reversing the disrupted MyHC phenotype in CKD is a potential therapeutic target for CKD-induced muscle atrophy.

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Establishment and validation of downsized hollow-fibre infection model and pharmacokinetics/pharmacodynamics analysis of VAN on Enterococcus faecium.

Hayashi Y, Takahashi M, Sasaki M, Suzuki K, Mizukami Y, Liu X, Enoki Y, Taguchi K, Yamaguchi T, Tateda K, Matsumoto K

The Journal of antimicrobial chemotherapy 80 （ 8 ） 2092 - 2099 2025年05月

共著,  ISSN  0305-7453

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Objectives This study clarified the target values of VAN against Enterococcus faecium using pharmacokinetics/pharmacodynamics (PK/PD) analysis and compared a downsized hollow fibre infection model (HFIM) with a conventional HFIM. Methods VAN was administered subcutaneously and blood concentrations were measured to calculate the PK parameters. PD studies were performed in an infected mouse model by administering VAN at doses ranging from 25 to 400 mg/kg based on PK parameters. PK/PD parameters correlated with antimicrobial efficacy were determined, and a target value of 2 log<inf>10</inf> kills was calculated. The efficacy of VAN against E. faecium was evaluated by reproducing the VAN PK in the plasma at doses that achieved the target value using conventional and novel downsized HFIMs. Results PK/PD analysis showed that fAUC/minimum inhibitory concentration (MIC) demonstrated the most relevant index, with a target value of 249 to achieve a 2 log<inf>10</inf> kill. Blood concentrations of 750 mg VAN every 12 h (equivalent to 260 fAUC/MIC) were simulated well with both HFIMs. Changes in E. faecium caused by continuous exposure to VAN resulted in a reduction in bacterial counts by ∼6.0 log<inf>10</inf> kill 168 h after the start of treatment in both models. Downsizing reduced the extracapillary space volume, circulating medium, amount of drugs used and infectious waste. The total cost of the downsized cartridge system was approximately half that of the conventional model system. Conclusions We established a downsized HFIM and demonstrated its viability as a cost-effective and environmentally sustainable in vitro PK/PD. The findings highlighted its potential as a future PK/PD analysis standard.

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Shortening the interval between the first and the second dose of vancomycin facilitates rapid achievement of the target AUC without increasing the risk of acute kidney injury, provided the AUC on the second day is appropriately controlled: a multicenter retrospective study.

Ishigo T, Suzuki A, Ibe Y, Fujii S, Fukudo M, Yoshida H, Tanaka H, Fujihara H, Yamaguchi F, Ebihara F, Maruyama T, Hamada Y, Yagi Y, Samura M, Nagumo F, Komatsu T, Tomizawa A, Takuma A, Chiba H, Nishi Y, Enoki Y, Taguchi K, Matsumoto K

Journal of pharmaceutical health care and sciences 11 （ 1 ） 44 2025年05月

共著,  ISSN  2055-0294

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Background: The impact of shortening or extending a vancomycin dosing interval on early attainment of target blood levels and acute kidney injury (AKI) remains unclear. We investigated the relationship between the interval of the first and second doses of vancomycin and early area under the concentration-time curve (AUC) and AKI. Methods: Patients (≥ 18 years) who started vancomycin and had trough/peak blood samples were included. The definition of shortened interval as the first and second doses of vancomycin was < 12 h. The cumulative incidence of AKI within 21 days was compared using the shortened interval and AUC on day 1 and 2. Results: Among 668 patients (median age 69 [interquartile range (IQR): 57, 78] years, 40% female), the proportion achieving an AUC ≥ 400 µg·h/mL on day 1 was significantly higher in the shortened-interval group (82% vs. 50%; p < 0.001). Multivariate analysis revealed no association between a shortened interval (hazards ratio [HR], 1.10 [95% confidence interval (CI), 0.63–1.91]; p = 0.750) or an AUC > 600 µg·h/mL on day 1 alone (HR, 2.17 [95% CI, 0.64–7.42]; p = 0.220) and AKI onset. However, an AUC > 600 µg·h/mL on day 2 alone (HR, 2.92 [95% CI, 1.45–5.87]; p = 0.003) or on both days (HR, 11.18 [95% CI, 5.07–24.67]; p < 0.001) was significantly associated with increased AKI risk. Conclusions: Shortening the dosing interval facilitates early achievement of target AUC without increasing AKI risk, provided AUC on day 2 is appropriately controlled.

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External validation of a flowchart related to achieving the target area under the concentration-time curve for vancomycin: A retrospective multicenter study

Ishigo T., Suzuki A., Ibe Y., Fujii S., Fukudo M., Yoshida H., Tanaka H., Fujihara H., Yamaguchi F., Ebihara F., Maruyama T., Yagi Y., Hamada Y., Samura M., Nagumo F., Komatsu T., Tomizawa A., Takuma A., Chiba H., Nishi Y., Igarashi Y., Enoki Y., Matsumoto K.

Journal of Infection and Chemotherapy 31 （ 5 ） 102701 2025年05月

共著,  ISSN  1341321X

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During therapeutic drug monitoring (TDM) for vancomycin (VCM), the area under the concentration-time curve (AUC) is important for balancing efficacy versus toxicity. In a previous study, we developed a decision tree (DT) model to achieve the target AUC during TDM over the follow-up period (AUCfollow-up). This study aimed to validate the DT model for achieving the target AUCfollow-up. Patients who received VCM for at least 72 h and had an initial TDM within four doses between January 2023 and December 2023 were analyzed. The AUC of the initial TDM was calculated over 2-point (peak/trough) concentrations via Bayesian estimation. The target AUCfollow-up was defined as 400–600 μg h/mL. Among 188 patients (median age [interquartile range], 66 [56, 79] years; 50 % female), the target AUCfollow-up was achieved in 70 % (132/188). When the predicted AUC was 400–600 μg h/mL, 84 % (102/121) achieved the target AUCfollow-up. In a 12 h dosing interval subgroup, 86 % (88/102) achieved the target AUCfollow-up. Conversely, when the predicted AUC was <400 or >600 μg h/mL, the proportion who achieved the target AUCfollow-up dropped to 44 % (30/67). Only 30 % (3/10) of those with creatinine clearance rates of >130 mL/min/1.73 m2 achieved the target. The area under the receiver operating characteristics curve was 0.74, and the R2 value was 0.15. Our findings confirmed the external validity of the DT model and supported its use for optimizing VCM dosing. Overall, the DT model offers a reliable framework for achieving target AUC values during follow-up for TDM, aiding safe and effective treatment.

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Efficacy of De-Escalation to Cefmetazole in Patients with Bacteremic Urinary Tract Infections Caused by Extended-Spectrum β-Lactamase-Producing Escherichia coli

Namiki T., Yokoyama Y., Kimura M., Fukuda S., Seyama S., Iketani O., Uwamino Y., Jibiki A., Kawazoe H., Ohtani H., Hasegawa N., Matsumoto K., Oda R., Hashi H., Suzuki S., Nakamura T.

Biological and Pharmaceutical Bulletin （公益社団法人 日本薬学会）  48 （ 5 ） 537 - 544 2025年05月

共著,  ISSN  09186158

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This study aimed to clarify the optimal value for the unbound cefmetazole concentration to remain above the minimum inhibitory concentration (MIC) (fT≥MIC) for efficacy of de-escalation to cefmetazole in patients with bacteremic urinary tract infection by extended-spectrum β-lactamase-producing Escherichia coli. This double-center retrospective observational study was conducted at Tokyo Bay Urayasu Ichikawa Medical Center and Keio University Hospital from January 2012 to October 2022. Efficacy was determined via clinical evaluation (mortality rate, recurrence rate, vital changes) and bacteriological evaluation, and the optimal fT≥MIC was calculated via receiver operating characteristic curve analysis. As a result, the number of patients evaluated were 40 (35 and 5 in the treatment success and treatment failure groups, respectively). Univariate analysis showed that fT≥MIC, recurrence rate, and MIC for cefmetazole against bacteria were significantly different for the two groups (p<0.05). Receiver operating characteristic curve analysis showed that the optimal fT≥MIC indicating efficacy was 57% (area under the curve: 0.94, 95% confidence interval: 0.86–1.00, p=0.002). All patients with fT≥MIC ≥ 57% had successful treatment, whereas the frequency of treatment failure was high among those with fT≥MIC <57%. The optimal fT≥MIC for the clinical efficacy of de-escalation to cefmetazole in patients with bacteremic urinary tract infection by extended-spectrum β-lactamase-producing E. coli was fT≥MIC ≥ 57%. This finding would be useful for optimal dosing of cefmetazole.

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Methemoglobin-Encapsulating Liposome: A Low-Risk Intravascular Contrast Agent for Magnetic Resonance Imaging

Taguchi K., Sumiyoshi A., Suzuki Y., Ozawa Y., Iiyama M., Gao S., Sakai H., Osada K., Matsumoto K., Aoki I.

ACS Applied Bio Materials 8 （ 4 ） 2838 - 2846 2025年04月

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Hemoglobin shows different contrasts on magnetic resonance imaging (MRI) depending on the iron and oxygenation states of heme. Functional brain MRI utilizes the differences in the concentrations of oxyhemoglobin and deoxyhemoglobin in cerebral blood vessels; blood clots produce strong magnetic susceptibility effects. We hypothesized that methemoglobin (MetHb)-based nanoparticles can act as MRI contrast agents because MetHb levels in red blood cells affect relaxivity and are strictly regulated to <1% in the blood. Herein, we describe the synthesis of methemoglobin-encapsulated liposomes (Met-HbVs) as contrast agents for MRI. Met-HbV, with a size of approximately 200 nm, increased longitudinal relaxivity (r1) by 2.44-fold compared with hemoglobin-encapsulated liposomes in vitro. In contrast, the transverse relaxation capacity (r2) of Met-HbVs was similar to that of the hemoglobin-encapsulated liposomes. Owing to its relaxivity, Met-HbV enhanced the signal intensity on T1-weighted images and angiography, especially in the veins. Furthermore, deleterious biological responses were seldom observed after Met-HbV administration in mice with chronic renal failure. In conclusion, Met-HbV possesses potential as a vascular contrast agent in MRI for angiography, with advantages over gadolinium-based contrast agents in terms of safety for patients with renal failure. To the best of our knowledge, this is the first report demonstrating the potential of MetHb as a biomaterial for contrast agents in MRI.

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Influence factors of metronidazole-related CNS disorders: an analysis of the Japan adverse drug event report and FDA adverse event reporting system.

Takada K, Enoki Y, Samura M, Igarashi Y, Taguchi K, Tanikawa K, Matsumoto K

Expert opinion on drug safety    1 - 7 2025年04月

共著,  ISSN  1474-0338

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Background: Metronidazole (MNZ) can be administered for various infections. The impact of comorbidities/concomitant drugs on MNZ-induced central nervous system (CNS) disorders remains unclear. Research design and methods: We assessed the risk of metronidazole-related CNS disorders using the Japan Adverse Drug Event Report (JADER, May 2023) and the US Food and Drug Administration Adverse Event Reporting System (FAERS, Q1 2023), excluding comorbidities/concomitant drugs. Clonazepam and diazepam were evaluated as potential prophylactics based on the efficacy of benzodiazepines for MNZ-related CNS disorders. Reporting odds ratios (ROR) and 95% confidence intervals (CI) were calculated. Additionally, sensitivity analysis by sex and age was conducted. Results: The ROR (95% CI) of CNS disorders associated with MNZ in JADER and FAERS were 3.16 (2.69–3.72) and 1.69 (1.64–1.73), respectively. MNZ was significantly related to CNS disorders after excluding comorbidities (brain/spinal cord or liver abscesses) and concomitant drugs (glucocorticoids, antiepileptic, antiparkinson, and schizophrenia drugs). In sensitivity analysis, MNZ was significantly related to CNS disorders, despite sex and age. The ROR in the concomitant with clonazepam (CZP) was 0.70 (0.53–0.92) in FAERS. Conclusion: MNZ may be associated with CNS disorders, even if comorbidities/concomitant drugs that are potential risk factors for CNS disorders are excluded. Additionally, CZP may suppress CNS disorders.

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医療用一般用共用医薬品(仮称)の創設提言に対する薬剤師の認知および見解に関する実態把握調査

岡本 侑子, 田口 和明, 榎木 裕紀, 堀 里子, 山浦 克典, 松元 一明

医療薬学 （(一社)日本医療薬学会）  51 （ 4 ） 196 - 202 2025年04月

共著,  ISSN  1346-342X

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日本薬剤師会が「政策提言2022」で提言した医療用一般用共用医薬品(仮称)の創設に対する薬剤師の認知や見解を明らかにするため、2024年1月に病院・保険薬局・ドラッグストアに勤務する薬剤師595人を対象にwebリサーチシステムを用いて無記名自己記入式質問紙調査を実施した。対象者の95%以上は病院または保険薬局に勤務している薬剤師で、約85%が30歳代から50歳代であり、医療用一般用共用医薬品の創設提言が行われたことを認知している対象者は職務に関係なく約30%であった。医療用一般用共用医薬品の認知の有無にかかわらず、対象者の過半数が医療用一般用共用医薬品の創設に賛成しており、医療用一般用共用医薬品の候補として感冒・鎮咳去痰薬や解熱鎮痛薬、整腸薬、シップを含む外用薬、抗アレルギー薬などが挙げられた。

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Direct comparison of the effects of first- and second-generation H(1) -receptor blockers on motor functions in mice.

Taguchi K, Tenjin K, Sakamoto Y, Shimada A, Hara R, Iketani O, Okamoto Y, Enoki Y, Kizu J, Hori S, Matsumoto K

Die Pharmazie 80 （ 1 ） 24 - 28 2025年03月

共著,  ISSN  0031-7144

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Development and validation of a population pharmacokinetic model of vancomycin for patients of advanced age.

Takada K, Samura M, Igarashi Y, Suzuki A, Ishigo T, Fujii S, Ibe Y, Yoshida H, Tanaka H, Ebihara F, Maruyama T, Hamada Y, Komatsu T, Tomizawa A, Takuma A, Chiba H, Yagi Y, Nishi Y, Enoki Y, Taguchi K, Tanikawa K, Kunishima H, Matsumoto K

Journal of pharmaceutical health care and sciences 11 （ 1 ） 18 2025年03月

共著,  ISSN  2055-0294

　概要を見る

Background: Population pharmacokinetic (PPK) models of vancomycin (VCM) commonly use creatinine clearance (CLcr) as a covariate for clearance (CL). However, relying on CLcr in patients of advanced age may lead to inaccuracies in estimating VCM clearance. Therefore, this study aimed to develop and validate a new PPK model specifically for patients aged 75 years and older. Methods: PPK analysis was performed based on the blood concentrations of VCM (n = 159 patients). The predictive performance of the developed model was compared with that of previous models using mean absolute error (MAE) and mean squared error (MSE) for another dataset. Results: The PPK analysis optimized a two-compartment model using CLcr and the Alb levels as covariates at the central compartment of VCM clearance. The final model was as follows: CL (L/h) = 1.96 × (CLcr/3.09) 0.63 × (Serum albumin (Alb) /2.3) 0.22 × exponential (0.11). Clearance between the central and peripheral compartments (L/h) = 4.86. Central compartment volume of distribution (L) = 31.78. Peripheral compartment volume of distribution (L) = 53.64. The validation study revealed that compared with those of previous models (ranging from 0.67 to 0.79 L/h and from 0.81 to 1.11 (L/h)2, respectively), the final model demonstrated the smallest MAE of 0.60 L/h and MSE of 0.65 (L/h)2 for patients of advanced age with serum creatinine levels of < 0.6 mg/dL. Conclusion: The PPK model of VCM for patients of advanced age was optimized by adding the Alb levels and CLcr as covariates for CL. The predictive accuracy of the PPK model for patients with an SCr of < 0.6 mg/dL tended to be higher than those of previous models based just on CLcr. Thus, dosage is suggested to be adjusted based on CLcr and Alb levels for patients with an SCr of < 0.6 mg/dL.

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Carbon monoxide alleviates endotoxin-induced acute lung injury via NADPH oxidase inhibition in macrophages and neutrophils

Watabe Y., Giam Chuang V.T., Sakai H., Ito C., Enoki Y., Kohno M., Otagiri M., Matsumoto K., Taguchi K.

Biochemical Pharmacology 233   116782 2025年03月

共著,  ISSN  00062952

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Sepsis is a life-threatening condition caused by severe infection and often complicates acute respiratory distress syndrome (ARDS) and acute lung injury (ALI) due to the collapse of the oxidative and inflammatory balance induced by microbial pathogens, including lipopolysaccharides (LPS). In sepsis-related ARDS/ALI, NADPH oxidase (NOX) and toll-like receptors (TLR) in neutrophils and macrophages are key players in initiating oxidative and inflammatory imbalances. Although NOX and TLR activation has been linked to carbon monoxide (CO), the mechanism by which CO affects sepsis-related ARDS/ALI through NOX and TLR remains unknown. Here, we demonstrate that CO reduces sepsis-related ARDS/ALI by inhibiting NOX in neutrophils and macrophages, which in turn suppresses the production of reactive oxygen species (ROS), TLR4-associated inflammatory responses, and macrophage polarization toward M1-like macrophages. CO-bound hemoglobin vesicle (CO-HbV) therapy, a hemoglobin-based CO donor, exerts a protective effect against LPS-induced ALI by suppressing exaggerated oxidative and inflammatory responses and neutrophil and M1-like macrophage infiltration in the bronchoalveolar lavage fluid (BALF). Through suppression of NOX activity, CO decreased ROS generation, the TLR4/NF-κB signaling pathway, and macrophage polarization toward M1-like macrophages, according to cellular experiments conducted with peripheral neutrophils, BALF cells, and Raw264.7 cells. Moreover, ALI was found to be more severe in Hmox1+/- mice (mice with decreased endogenous CO production) than in the wild-type mice. Our findings suggest that both endogenously generated and exogenously supplied CO inhibit NOX-associated ROS generation, the TLR4/NF-κB signaling pathway, and macrophage polarization, thereby eliciting antioxidant and anti-inflammatory responses that prevent the onset and progression of LPS-induced ALI.

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The combined dual β-lactams and diazabicyclooctane β-lactamase inhibitor is highly effective against Mycobacterium abscessus species in vitro.

Misawa K, Nishimura T, Yoshikawa M, Shimamura R, Kashimura S, Enoki Y, Taguchi K, Matsumoto K, Hasegawa N

Journal of global antimicrobial resistance 42   142 - 150 2025年02月

共著,  ISSN  2213-7165

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Objective: Mycobacterium abscessus pulmonary disease is a refractory infectious disease. Developing an effective treatment is urgent as the number of patients infected with M. abscessus species (MABS) is increasing worldwide. We previously reported that nacubactam, a diazabicyclooctane (DBO) β-lactamase inhibitor, could inhibit MABS β-lactamase. Few reports have indicated that dual β-lactams are effective with a DBO β-lactamase inhibitor against MABS. The objective of this study was to determine which dual β-lactams have high antibacterial activity against MABS in the presence and absence of nacubactam. Methods: Antimicrobial susceptibility tests were conducted through a checkerboard assay of 27 β-lactams using the broth microdilution method for three subspecies-type strains and 20 clinical isolates of MABS. The number of intracellular and extracellular bacteria was measured using human macrophages infected with M. abscessus treated with effective combinations confirmed in susceptibility tests. Results: In antimicrobial susceptibility tests, 91 combinations of dual β-lactams with nacubactam exhibited synergistic effects on M. abscessus JCM13569. Among them, the combination of cefazolin, cefotiam, cefoxitin, or cefuroxime with imipenem and nacubactam exhibited highly synergistic effects, resulting in low MICs against MABS clinical isolates. Without nacubactam, the combination of imipenem and cefoxitin showed the lowest MIC. In experiments using human macrophages infected with M. abscessus, these dual β-lactam combinations reduced the number of intracellular and extracellular bacteria compared with those of single β-lactams. Conclusions: The combination of cefazolin, cefotiam, cefoxitin, or cefuroxime with imipenem and nacubactam was highly effective against MABS. Without nacubactam, the combination of cefoxitin and imipenem was effective.

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In Vitro Activity of Aztreonam in Combination with Relebactam against Gram-Negative Pathogens Producing Various Serine and Metallo-β-Lactamases.

Hayashi K, Suzuki M, Ishii Y, Matsumura Y, Matsumoto K, Saito S, Doi Y

Journal of global antimicrobial resistance 42   73 - 79 2025年02月

共著,  ISSN  2213-7165

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Objectives: Infections caused by carbapenemase-producing Gram-negative pathogens have become a significant global public health challenge due to limited treatment options. Pathogens producing metallo-β-lactamase are particularly problematic since they are not inhibited by conventional β-lactamase inhibitors. Herein, we assess the in vitro activity of aztreonam in combination with relebactam against a collection carbapenemase producing organisms, including strains producing both serine‑β-lactamase and IMP-type metallo-β-lactamase that are commonly encountered in Japan. Methods: A total of 119 carbapenemase-producing clinical isolates were used in this study. Minimum inhibitory concentrations (MICs) of aztreonam and imipenem alone and aztreonam/relebactam, aztreonam/avibactam and imipenem/relebactam combinations were determined by the broth microdilution method. Results: Aztreonam MICs were reduced in combination with relebactam for strains producing ESBL or AmpC in addition to IMP-type, NDM-type, GES-type or OXA-48 carbapenemases and for Stenotrophomonas spp. Additionally, aztreonam/relebactam combination MICs were significantly lower than MICs of aztreonam alone among IMP producers, NDM producers and Stenotrophomonas spp. Significant differences between aztreonam/relebactam and aztreonam MICs were also observed for strains of E. coli, K. pneumoniae and Enterobacter spp., many of which produced both metallo-β-lactamase and serine‑β-lactamase. The aztreonam/relebactam combination showed comparable to higher MICs compared with the aztreonam/avibactam combination. Conclusion: The addition of relebactam has a potential to restore the activity of aztreonam against strains that produce metallo-β-lactamase and serine‑β-lactamase. The combination may have a role in the treatment of infections due to these strains in countries without access to ceftazidime-avibactam.

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