Details of a Researcher - IGARASHI Yuki

Papers - IGARASHI Yuki

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Application of epithelial lining fluid drug concentrations to MICi-Based PK/PD modeling of cefepime/nacubactam in a murine model of CPE pneumonia

Yuki Mizukami, Mishu Takahashi, Kenta Suzuki, Shaoqing Duan, Shintaro Ikegami, Takuma Muraishi, Natsuki Satake, Yuko Okamoto, Yuki Igarashi, Yuki Enoki, Kazuaki Taguchi, Kazuaki Matsumoto

Journal of Infection and Chemotherapy 32 ( 1 ) 102889 2026.01

Research paper (scientific journal), Corresponding author, Accepted

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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 2025.12

Research paper (scientific journal), Accepted, ISSN 1341321X

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 31 ( 11 ) 102821 2025.11

Research paper (scientific journal), Accepted, ISSN 1341321X

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 (r<sup>2</sup> = 0.965, p < 0.001). Seventeen cases (6.6 %) showed discrepancies ≥10 %. Multivariate analysis identified BMI ≥25 kg/m<sup>2</sup> (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

Ayano Kawasaki, Ryuya Shintani, Risa Takao, Yuka Nakazawa, Takayuki Mihara, Shintaro Ikegami, Sora Shimada, Yuri Matsumoto, Yuko Okamoto, Yuki Igarashi, Yuki Enoki, Kazuaki Taguchi, Kazuaki Matsumoto

Medical Mycology (Oxford University Press) 63 ( 10 ) myaf089 2025.09

Research paper (scientific journal), Joint Work, Corresponding author, Accepted, ISSN 13693786

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

Maiko Yoshikawa, Tomoyasu Nishimura, Kana Misawa, Rina Shimamura, Kenta Suzuki, Shoko Kashimura, Yuki Igarashi, Yuki Enoki , Kazuaki Taguchi, Naoki Hasegawa, Ho Namkoong, Kazuaki Matsumoto

Microbiology Spectrum 13 ( 11 ) e0201225 - 15 2025.09

Research paper (scientific journal), Joint Work, Accepted

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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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 ) 102701 2025.05

Research paper (scientific journal), 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.

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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 3 1 - 7 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.

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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 2025.03

Research paper (scientific journal), 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.

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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 ) 102485 2025.01

Research paper (scientific journal), 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.

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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

Research paper (scientific journal), 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.

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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

Research paper (scientific journal), 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%.

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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

Research paper (scientific journal), 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.

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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

Research paper (scientific journal), 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.

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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

Research paper (scientific journal), Accepted, 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.

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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

Research paper (scientific journal), Accepted, 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.

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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

Research paper (scientific journal), Accepted, ISSN 22137165

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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

Research paper (scientific journal), Accepted, 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%.

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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

Research paper (scientific journal), 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

Research paper (scientific journal), 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 24 ( 11 ) 907 - 914 2018.08

Research paper (scientific journal), Lead author, Accepted

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