Details of a Researcher - Matsumoto, Kazuaki

Papers - Matsumoto, Kazuaki

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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 2025.06

Joint Work, ISSN 0732-8893

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 2025.06

Joint Work, ISSN 0022-3573

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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 2025.06

Joint Work

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 2025.05

Joint Work, ISSN 0305-7453

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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 2025.05

Joint Work, ISSN 2055-0294

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 2025.05

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

Namiki Takaya, Yokoyama Yuta, Kimura Motonori, Fukuda Shogo, Seyama Shoji, Iketani Osamu, Uwamino Yoshifumi, Jibiki Aya, Kawazoe Hitoshi, Ohtani Hisakazu, Hasegawa Naoki, Matsumoto Kazuaki, Oda Rentaro, Hashi Hideki, Suzuki Sayo, Nakamura Tomonori

Biological and Pharmaceutical Bulletin (The Pharmaceutical Society of Japan) 48 ( 5 ) 537 - 544 2025.05

Joint Work, ISSN 09186158

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.

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 2025.04

Joint Work

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 2025.04

Joint Work, ISSN 1474-0338

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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Pharmacists’ Awareness and Support for Common-use Pharmaceuticals: A Survey Study

Okamoto Yuko, Taguchi Kazuaki, Enoki Yuki, Hori Satoko, Yamaura Katsunori, Matsumoto Kazuaki

Iryo Yakugaku (Japanese Journal of Pharmaceutical Health Care and Sciences) (Japanese Society of Pharmaceutical Health Care and Sciences) 51 ( 4 ) 196 - 202 2025.04

Joint Work, ISSN 1346-342X

The Japan Pharmaceutical Association proposed a new category of over-the-counter (OTC) drugs, tentatively termed “common-use pharmaceuticals for both medical and general use,” in their “Policy Proposal 2022.” This new category will be classified as “Class 0,” meaning the risk classification will remain unchanged. Consequently, pharmacists will be responsible for providing information and selling these products. Understanding pharmacists’ perceptions of this policy proposal is crucial for developing a framework for this new category; however, no relevant evidence exists. Therefore, this study conducted a web-based, anonymous, self-administered questionnaire survey targeting pharmacists in hospitals, health insurance pharmacies, and drugstores to investigate their awareness and views on the proposal. The results revealed that less than 30％ of the pharmacists, regardless of their job role (hospital, health insurance pharmacy, or drugstore), were aware of the proposal, indicating a low level of awareness. However, regardless of their awareness at the time of the survey, more than half of the respondents expressed support for establishing these common-use pharmaceuticals, with few opposing the idea. Many pharmacists identified cold remedies, antitussives/expectorants, antipyretic analgesics, digestive medications, topical medications (eg, patches), and allergy medications as medical drugs that should be classified under the new category. This study is the first to offer insight into pharmacist awareness and views regarding the establishment of common-use pharmaceuticals, providing evidence for future discussions.

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 2025.03

Joint Work, 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 2025.03

Joint Work, ISSN 2055-0294

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 2025.03

Joint Work, ISSN 00062952

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 2025.02

Joint Work, ISSN 2213-7165

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 2025.02

Joint Work, ISSN 2213-7165

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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Reply to Mitsuboshi, "Enhancing result reliability by addressing potential confounding factors".

Ishigo T, Matsumoto K, Yoshida H, Tanaka H, Ibe Y, Fujii S, Fukudo M, 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, Suzuki A

Microbiology spectrum 13 ( 3 ) e0149924 2025.02

Joint Work

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Evaluation of lung epithelial lining fluid concentrations of lascufloxacin against Streptococcus pneumoniae in a hollow-fiber infection model

Kamura H.N., Yamaguchi T., Kasama T., Hayashi Y., Hamada M., Matsumoto K., Miyake R., Ishii Y.

Journal of Antibiotics 78 ( 6 ) 388 - 391 2025

Joint Work, ISSN 00218820

Lascufloxacin (LSFX) achieves concentrations in epithelial lining fluid (ELF) that are more than 15 times higher than those in the bloodstream, making it a promising candidate for respiratory and otorhinolaryngological infections. These concentrations were replicated using the Hollow-Fiber Infection Model and demonstrated bactericidal efficacy of LSFX against levofloxacin-sensitive and -resistant Streptococcus pneumoniae. The study confirms that LSFX’s elevated concentration in ELF plays a significant role in its bactericidal activity.

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Treatment success prediction in patients with methicillin-resistant coagulase-negative staphylococci infections, using vancomycin AUC24/MIC ratio: a multicentre retrospective cohort study.

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

The Journal of antimicrobial chemotherapy 80 ( 2 ) 538 - 546 2024.12

Joint Work, ISSN 0305-7453

Background: Although vancomycin is commonly used to treat methicillin-resistant coagulase-negative staphylococci (MRCoNS) infections, there are no clear guidelines for the optimal 24 h AUC24/MIC ratio. This study aimed to determine the target AUC24/MIC ratio associated with vancomycin-treated MRCoNS infection outcomes. Methods: This multicentre retrospective cohort study included adult patients who received vancomycin for ≥5 days for bloodstream infections caused by MRCoNS between January 2018 and December 2023. 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 was used to identify the AUC24/MIC cut-off for treatment success. Multivariate regression analysis was used to determine the association between AUC24/MIC and outcomes. Results: This study included 147 patients. ROC analysis identified a target AUC24/MIC ≥373 for treatment success. The overall treatment success rate (70.1%) was significantly higher in the above-average AUC24/MIC cutoff group (83.1%) than that in the below AUC24/MIC cut-off group (57.9%). Multivariate analysis confirmed that AUC24/MIC ≥373 was an independent predictor (adjusted OR = 10.227; 95% CI = 3.585–29.171). The 30-day mortality and microbiological eradication rates differed significantly between the below- and above-cut-off groups, whereas nephrotoxicity rates were comparable among the groups. Conclusions: In treating MRCoNS infections, vancomycin AUC24/MIC ratio ≥373 was independently associated with favourable treatment outcomes. However, further prospective studies are required to confirm this target owing to the retrospective nature of this study.

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

Igarashi Y, Taguchi K, Enoki Y, Chuang VTG, Matsumoto K

The Journal of antimicrobial chemotherapy 80 ( 2 ) 547 - 553 2024.12

Joint Work, ISSN 0305-7453

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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Bacteremia and meningitis caused by penicillin-resistant Streptococcus pneumoniae serotype 35B successfully treated with ceftriaxone combined with vancomycin followed by linezolid: A case report

Tomioka Mifumi, Nakamura Kiwamu, Duan Shaoqing, Matsumoto Kazuaki, Shindo Takahiro, Hoshi Keisuke, Nagao Mika, Oshima Fuminari, Hara Yasuka, Namai Yoshiyuki

Internal Medicine (The Japanese Society of Internal Medicine) advpub ( 0 ) 1761 - 1766 2024.11

Joint Work, ISSN 0918-2918

We herein report a case of bacterial meningitis and bacteremia in a 3-month-old boy caused by Streptococcus pneumoniae serotype 35B multidrug resistance. Intravenous ampicillin was administered on admission. However, when pneumococcal meningitis was suspected, the antibiotic treatment was changed to ceftriaxone (CTRX) and vancomycin (VCM). However, owing to difficulties in achieving sufficient serum trough levels of VCM, this treatment was again switched to linezolid (LZD). The patient recovered without complications after 16 days of CTRX and LZD treatment. This case suggests that LZD is a viable treatment option for bacterial meningitis.

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