Details of a Researcher - Igarashi, Yuki

Papers - Igarashi, Yuki

Division display >> ／ All the affair displays 1 - 15 of about 15

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

Tomoyuki Ishigo, Ayako Suzuki, Yuta Ibe, Satoshi Fujii, Masahide Fukudo, Hiroaki Yoshida, Hiroaki Tanaka, Hisato Fujihara, Fumihiro Yamaguchi, Fumiya Ebihara, Takumi Maruyama, Yusuke Yagi, Yukihiro Hamada, Masaru Samura, Fumio Nagumo, Toshiaki Komatsu, Atsushi Tomizawa, Akitoshi Takuma, Hiroaki Chiba, Yoshifumi Nishi, Yuki Igarashi, Yuki Enoki, Kazuaki Matsumoto

Journal of Infection and Chemotherapy 31 ( 5 ) 2025.05

Accepted, ISSN 1341321X

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.

Access to Document (DOI)

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 2025.04

Research paper (scientific journal), Accepted, ISSN 14740338

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.

Access to Document (DOI)

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 ) 2025.03

Accepted

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.

Access to Document (DOI)

SARS-CoV-2 mRNA vaccine-related myocarditis and pericarditis: An analysis of the Japanese Adverse Drug Event Report database.

Keisuke Takada, Kazuaki Taguchi, Masaru Samura, Yuki Igarashi, Yuko Okamoto, Yuki Enoki, Koji Tanikawa, Kazuaki Matsumoto

Journal of Infection and Chemotherapy 31 ( 1 ) 2025.01

Accepted, ISSN 1341321X

Background: The association between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccines and myocarditis/pericarditis in the Japanese population has not been systematically investigated. This study was aimed at clarifying the association between SARS-CoV-2 mRNA vaccines (BNT162b2 and mRNA-1273) and myocarditis/pericarditis as well as influencing factors by using the Japanese Adverse Drug Event Report database. Methods: Reporting odds ratios (RORs) and 95 % confidence intervals (95 % CIs) for the association between the vaccines and myocarditis/pericarditis were calculated using data from the database (April 2004–December 2023). Age, sex, onset time, and outcomes in symptomatic patients were evaluated. Results: The total number of reports was 880,999 (myocarditis: 1846; pericarditis: 761). The adverse events associated with the vaccines included myocarditis (919 cases) and pericarditis (321 cases), with the ROR [95 % CIs] being significant for both (myocarditis: 30.51 [27.82–33.45], pericarditis: 21.99 [19.03–25.40]). Furthermore, the ROR [95 % CIs] of BNT162b2 and mRNA-1273 were 15.64 [14.15–17.28] and 54.23 [48.13–61.10], respectively, for myocarditis, and 15.78 [13.52–18.42] and 27.03 [21.58–33.87], respectively, for pericarditis. Furthermore, most cases were ≤30 years or male. The period from vaccination to onset was ≤8 days, corresponding to early failure type based on analysis using the Weibull distribution. Outcomes were recovery or remission for most cases; however, they were severe or caused death in some cases. Conclusion: In the Japanese population, SARS-CoV-2 mRNA vaccination was significantly associated with the onset of myocarditis/pericarditis. The influencing factors included age of ≤30 years and male. Furthermore, although most adverse events occurred early after vaccination, overall outcomes were good.

Access to Document (DOI)

Simulated achievement rate of β-lactams/nacubactam treatment in humans using instantaneous MIC-based PK/PD analysis.

Yuki Igarashi, Kazuaki Taguchi, Yuki Enoki, Victor Tuan Giam Chuang, Kazuaki Matsumoto

Journal of Antimicrobial Chemotherapy 80 ( 2 ) 547 - 553 2024.12

Lead author, Accepted, ISSN 03057453

Background: Nacubactam (NAC), a new diazabicyclooctane β-lactamase inhibitor, is being developed for use together with aztreonam (AZT) and cefepime (CFPM). However, the effective clinical dosages of AZT/NAC and CFPM/NAC have not yet been established. We have previously shown that free time above instantaneous MIC (fT > MICi) is a valuable pharmacokinetic (PK)/pharmacodynamic parameter for β-lactam (BL)/NAC in a mouse thigh infection model. Objectives: This study simulated the fT > MICi (%) for AZT/NAC and CFPM/NAC against carbapenemase-producing Enterobacterales (CPE) with different MIC in humans to estimate the clinical efficacy at practically achievable combination doses of AZT/NAC and CFPM/NAC. Methods: Using previously reported PK parameters of each drug in humans and chequerboard MIC data, we calculated the fT > MICi (%) for AZT/NAC and CFPM/NAC in 10 000 simulated patients to predict the percentages of target attainment of bacteriostatic and bactericidal efficacies at various combined doses. Results: The results predicted that both BL/NAC combinations could achieve 100% 2 log10-kill against CPE strains at the lowest combination dose (0.5 g/0.5 g q8h). Additionally, in MIC studies examining BLs/NAC at a 1:1 ratio, the dosage regimen for strains with MICcomb ≤ 1 mg/L was expected to offer 100% bactericidal efficacy (2 log10-kill) at 0.5 g/0.5 g q8h or higher doses. For strains with 1 mg/L < MICcomb ≤ 16 mg/L, BLs/NAC at a 2 g/2 g q8h was predicted to produce bactericidal efficacy (1 log10-kill). At MICcomb = 32 mg/L, some bacteriostatic effect was expected at high BL doses. Conclusions: AZT/NAC and CFPM/NAC are bactericidal against CPE at practically achievable dosages.

Access to Document (DOI)

In vivo Pharmacokinetic/Pharmacodynamic Analysis of the Efficacy of the Cefepime/Nacubactam Combination Against β-Lactamase-Producing Enterobacterales based on the Instantaneous MIC Concept

Igarashi Y., Takemura W., Liu X., Kojima N., Morita T., Chuang V.T.G., Enoki Y., Taguchi K., Matsumoto K.

Pharmaceutical Research 40 ( 10 ) 2423 - 2431 2023.10

Lead author, Accepted, ISSN 07248741

Purpose: Nacubactam (NAC) is a novel diazabicyclooctane β-lactamase inhibitor used in combination with cefepime (CFPM). In this study, we aimed to determine the target pharmacokinetics (PK) and pharmacodynamics (PD) values of CFPM/NAC in mice infected with β-lactamase-producing Enterobacterales, such as the carbapenemase-producing Enterobacterales. Methods: Three strains of β-lactamase-producing Enterobacterales, Klebsiella pneumoniae MSC 21444, Escherichia coli MSC 20662, and K. pneumoniae ATCC BAA-1898, were used for checkerboard assays and fractionation studies and dose-range studies. A PK study was performed in neutropenic mice. Additionally, PK/PD analysis was performed based on the instantaneous minimum inhibitory concentration (MICi) concept. Results: Checkerboard measurements revealed that higher NAC concentrations decreased the CFPM MIC in a concentration-dependent manner. In all tested strains, fT > MICi calculated from the PK experiments showed a high correlation with the mean change in the bacterial count of thigh-infected mice in the in vivo PD study, suggesting that fT > MICi is an optimal PK/PD parameter for monitoring the CFPM/NAC combination. The target fT > MICi values for CFPM/NAC to achieve a bacteriostatic effect, 1-log10-kill, and 2-log10-kill values were 30, 49, and 94%, respectively. Conclusions: Our results indicate that fT > MICi is a PK/PD parameter is suitable for monitoring the CFPM/NAC combination. The minimum target value for achieving a static effect against β-lactamase-producing Enterobacterales is 30%.

Access to Document (DOI)

In vivo pharmacokinetics/pharmacodynamics profiles for appropriate doses of cefditoren pivoxil against S. pneumoniae in murine lung-infection model.

Yuki Igarashi, Nana Kojima, Wataru Takemura, Xiaoxi Liu, Takumi Morita, Yuki Mizukami, Yuki Enoki, Kazuaki Taguchi, Yuta Yokoyama, Tomonori Nakamura, Kazuaki Matsumoto

Pharmaceutical Research 40 ( 7 ) 1789 - 1797 2023.05

Lead author, Accepted, ISSN 07248741

Purpose: Cefditoren, the active form of cefditoren pivoxil, is an oral cephalosporin antimicrobial drug. Although cefditoren exhibits high antimicrobial activity against Streptococcus pneumoniae, its pharmacokinetics/pharmacodynamics (PK/PD) characteristics remain unknown. This study aimed to determine its PK/PD parameter with target values for cefditoren against S. pneumoniae in S. pneumoniae lung-infected mice and to simulate MIC range of S. pneumoniae that can be expected to be treated at approved cefditoren doses in human using population pharmacokinetic (PPK) data from patients. Methods: Susceptibility testing and time-kill assays against S. pneumoniae ATCC® 49619 were performed for in vitro PD evaluation. Based on the results of a PK study in healthy mice and PD studies in S. pneumoniae lung-infected mice, optimal PK/PD parameters were determined using the correlation curve between the PK/PD parameters and lung bacterial count changes. The target value was calculated to achieve a 2 log10 reduction in the lung bacterial counts. Results: In vitro PD evaluation showed that cefditoren had a potent antimicrobial effect against S. pneumoniae in a time-dependent manner at concentrations above the MIC. In PK/PD analyses, both fAUC24/MIC and fCmax/MIC were well correlated with bactericidal efficacy, achieving 2 log10-kill with fAUC24/MIC ≥ 63 and fCmax/MIC ≥ 16. Conclusions: Cefditoren pivoxil has good therapeutic efficacy against acute pneumonia caused by S. pneumoniae with a MIC ≤ 0.031–0.063 mg/L at approved doses in adults and children.

Access to Document (DOI)

Development of an optimized and practical pharmacokinetics/pharmacodynamics analysis method for aztreonam/nacubactam against carbapenemase-producing K. pneumoniae

Igarashi Y., Takemura W., Liu X., Kojima N., Morita T., Chuang V.T.G., Enoki Y., Taguchi K., Matsumoto K.

Journal of Antimicrobial Chemotherapy 78 ( 4 ) 991 - 999 2023.04

Lead author, Accepted, ISSN 03057453

Background: Nacubactam, a new β-lactamase inhibitor with antibacterial activity, is being developed as a single drug to be co-administered with cefepime or aztreonam. However, determining pharmacokinetics/pharmacodynamics (PK/PD) parameters in β-lactam/β-lactamase inhibitor combinations remains challenging. We aimed to establish a practical PK/PD analysis method for aztreonam/nacubactam that incorporates instantaneous MIC (MICi). Methods: Based on chequerboard MIC measurements, MICi of aztreonam against carbapenemase-producing Klebsiella pneumoniae in the presence of nacubactam was simulated. Results: The mean change in the bacterial count of thigh-infected mice in an in vivo PD study was plotted based on %fT>MICi and analysed using the inhibitory effect sigmoid Imax model. fT>MICi calculated from the PK experiments showed a high correlation with the in vivo bactericidal effect, suggesting that fT>MICi is the optimal PK/PD parameter for aztreonam/nacubactam. The target values of fT>MICi achieving growth inhibition, 1 log10 kill and 2 log10 kill, were 22, 38% and 75%, respectively. Conclusions: The PK/PD analysis method proposed in this study is promising for determining practical PK/PD parameters in combination therapy. In addition, this is the first report of aztreonam/nacubactam showing a potent in vivo therapeutic effect against NDM-producing K. pneumoniae.

Access to Document (DOI)

Differences in Pharmacokinetic/Pharmacodynamic Parameters of Tedizolid Against VRE and MRSA

Liu X., Tashiro S., Igarashi Y., Takemura W., Kojima N., Morita T., Hayashi M., Enoki Y., Taguchi K., Matsumoto K.

Pharmaceutical Research 40 ( 1 ) 187 - 196 2023.01

ISSN 07248741

Purpose: Vancomycin-resistant enterococci (VRE) have recently become a major cause of nosocomial infections and a global public health concern. Tedizolid exhibits powerful antibacterial activity against VRE in vitro, but its pharmacokinetic/pharmacodynamic (PK/PD) parameters remain unclear. Therefore, we aimed to determine the PK/PD indices of tedizolid action on VRE and the mechanisms underlying the PK/PD indices differences of tedizolid against VRE and methicillin-resistant Staphylococcus aureus (MRSA). Methods: Optimal PK/PD target values of tedizolid were determined in vitro, based on time-kill curves and post-antibiotic effects (PAEs), and in vivo, using mouse models of thigh infection with VRE and MRSA strains. Results: The tedizolid bactericidal activity on VRE and MRSA was time-dependent. Correlations were closest between fAUC24/MIC and the tedizolid PK/PD index against MRSA and VRE. To achieve 1 log10 kill tedizolid fAUC24/MIC in neutropenic mouse models of thigh infection with VRE and MRSA should be 14.2 and 138.5, respectively. The PAEs of tedizolid against VRE and MRSA were 2.39 and 0.99 h, respectively. Conclusion: Tedizolid showed bactericidal effects against VRE even in neutropenic mice unlike MRSA, which could be attributed to its longer PAE against VRE. Hence, we hypothesize that tedizolid treatment against VRE infections is promising for achieving therapeutic success in clinical.

Access to Document (DOI)

Cefmetazole as an Alternative to Carbapenems Against Extended-Spectrum Beta-Lactamase-Producing Escherichia coli Infections Based on In Vitro and In Vivo Pharmacokinetics/Pharmacodynamics Experiments

Takemura W., Tashiro S., Hayashi M., Igarashi Y., Liu X., Mizukami Y., Kojima N., Morita T., Enoki Y., Taguchi K., Yokoyama Y., Nakamura T., Matsumoto K.

Pharmaceutical Research 38 ( 11 ) 1839 - 1846 2021.11

ISSN 07248741

Purpose: Cefmetazole (CMZ) has received attention as a pharmaceutical intervention for extended-spectrum beta-lactamase-producing Escherichia coli (ESBL-EC) infections. This study aimed to investigate the pharmacokinetics/pharmacodynamics (PK/PD) characteristics of CMZ against ESBL-EC. Methods: The susceptibility and time-killing activity of CMZ against clinically isolated ESBL-EC (EC9 and EC19) were determined in vitro. The optimal PK/PD index and its target value were calculated based on the results of a PK study in healthy mice and PD study in neutropenic murine thigh infection model mice. Results: The minimum inhibitory concentrations (MICs) of CMZ against EC9 and EC19 were 2.0 and 1.0 µg/mL, respectively. Time–kill studies showed that colony-forming units decreased in a time-dependent manner at CMZ concentrations in the range of 4–64 × MIC. In in vivo PK/PD studies, the antibacterial effect of CMZ showed the better correlation with the time that the free drug concentration remaining above the MIC (fT>MIC), with the target values for a static effect and 1 log10 kill reduction calculated as 57.6% and 69.6%, respectively. Conclusion: CMZ possesses time-dependent bactericidal activities against ESBL-EC and is required to achieve “fT>MIC” ≥ 69.6% for the treatment of ESBL-EC infections.

Access to Document (DOI)

Remdesivir for the treatment of coronavirus COVID-19: A meta-analysis of randomised controlled trials

Enoki Y., Igarashi Y., Watabe Y., Honma K., Suzuki Y., Hayashi Y., Hiraoka K., Taguchi K., Matsumoto K.

Journal of Global Antimicrobial Resistance 24 81 - 82 2021.03

ISSN 22137165

Access to Document (DOI)

Pharmacokinetics/Pharmacodynamics Evaluation of Flomoxef against Extended-Spectrum Beta-Lactamase-Producing Escherichia coli In Vitro and In Vivo in a Murine Thigh Infection Model

Tashiro S., Hayashi M., Takemura W., Igarashi Y., Liu X., Mizukami Y., Kojima N., Enoki Y., Taguchi K., Yokoyama Y., Nakamura T., Matsumoto K.

Pharmaceutical Research 38 ( 1 ) 27 - 35 2021.01

ISSN 07248741

Purpose: Although flomoxef (FMOX) has attracted substantial attention as an antibiotic against extended-spectrum beta-lactamase-producing Escherichia coli (ESBL-producing E. coli), the pharmacokinetics/pharmacodynamics (PK/PD) characteristics of FMOX against ESBL-producing E. coli is unclear. The aim of this study was to determine the PK/PD index of FMOX against ESBL-producing E. coli. Methods: In vitro time-kill curve studies and in vivo PK/PD experiments were carried out. Results: Time–kill curves exhibited a unique bactericidal activity: time-dependent activity at low concentrations and concentration-dependent activity at high concentrations. In neutropenic murine thigh infection experiments, the antibacterial activity of FMOX correlated with the time that the free drug concentration remaining above the minimum inhibitory concentration (MIC) (fT>MIC) and the ratio of the area under the free drug concentration–time curve for a 24 h period to the MIC (fAUC24/MIC). However, the burden of ESBL producing E. coli significantly reduced when the time intervals for administration were shorter among three dosage regimens with same magnitude of fAUC24/MIC, indicating that fT>MIC is significant PK/PD index. The target value of fT>MIC for 1 log10 kill reduction was 35.1%. Conclusions: fT>MIC is the most significant PK/PD index of FMOX against ESBL-producing E. coli and its target value is ≥ 40%.

Access to Document (DOI)

Azoles versus conventional amphotericin B for the treatment of candidemia: a meta-analysis of randomized controlled trials.

Sumika Osa, Sho Tashiro, Yuki Igarashi, Yuki Watabe, Xiaoxi Liu, Yuki Enoki, Kazuaki Taguchi, Toshihiko Mayumi, Yoshitsugu Miyazaki, Yoshio Takesue, Kazuaki Matsumoto

Journal of Infection and Chemotherapy 26 ( 11 ) 1232 - 1236 2020.11

Accepted

Echinocandins versus non-echinocandins for the treatment of invasive candidiasis: a meta-analysis of randomized controlled trials.

Sho Tashiro, Sumika Osa, Yuki Igarashi, Yuki Watabe, Xiaoxi Liu, Yuki Enoki, Kazuaki Taguchi, Toshihiko Mayumi, Yoshitsugu Miyazaki, Yoshio Takesue, Kazuaki Matsumoto

Journal of Infection and Chemotherapy 26 ( 11 ) 1164 - 1176 2020.11

Accepted

Oral vancomycin versus metronidazole for the treatment of Clostridioides difficile infection: meta-analysis of randomized controlled trials.

Yuki Igarashi, Sho Tashiro, Yuki Enoki, Kazuaki Taguchi, Kazuaki Matsumoto, Hiroki Ohge, Hiromichi Suzuki, Atsushi Nakamura, Nobuaki Mori, Yoshitomo Morinaga, Yuka Yamagishi, Sadako Yoshizawa, Katsunori Yanagihara, Hiroshige Mikamo, Hiroyuki Kunishima

Journal of Infection and Chemotherapy 2018.08

Lead author, Accepted

　 Previous page - Next page 　