Details of a Researcher - Matsumoto, Kazuaki

Papers - Matsumoto, Kazuaki

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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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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 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 ) 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.

Development of a pharmacokinetic/pharmacodynamic evaluation model for osteomyelitis and usefulness of tedizolid as an alternative to vancomycin against MRSA osteomyelitis.

Liu X, Enoki Y, Taguchi K, Matsumoto K

The Journal of pharmacy and pharmacology 77 ( 2 ) 291 - 298 2024.11

Joint Work, ISSN 0022-3573

Objectives: This study aimed to develop a suitable osteomyelitis model for pharmacokinetic/pharmacodynamic (PK/PD) evaluation and to investigate the target PK/PD values of vancomycin and tedizolid against methicillin-resistant Staphylococcus aureus (MRSA) osteomyelitis. Methods: An osteomyelitis model was established by implanting an MRSA-exposed sterilized suture in the tibia of normal mice and mice with cyclophosphamide-induced neutropenia. The suitability of the osteomyelitis mouse model for PK/PD evaluation was assessed using vancomycin as an indicator. The target PK/PD values for tedizolid were determined using this model. Key findings: In neutropenic mice, to achieve a static effect and 1 log10 kill against MRSA, the ratios of the area under the free drug concentration-time curve for 24 h to the minimum inhibitory concentration (fAUC24/MIC) of vancomycin were 91.29 and 430.03, respectively, confirming the validity of the osteomyelitis model for PK/PD evaluation. In immunocompetent mice, the target fAUC24/MIC values of tedizolid for achieving a static effect and 1 log10 kill against MRSA were 2.40 and 49.20, respectively. Additionally, only a 0.28 log10 kill was achieved in neutropenic mice with 20 times the human equivalent dose of tedizolid. Conclusions: In patients with restored immunity, tedizolid can potentially be used as an alternative to intravenous vancomycin therapy.

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Investigating the hypothermic effects of fluoroquinolone antimicrobials on non-bacterial fever model mice.

Hara R, Taguchi K, Ogino H, Okamoto Y, Enoki Y, Kizu J, Hori S, Matsumoto K

Journal of pharmaceutical health care and sciences 10 ( 1 ) 68 2024.11

Joint Work, ISSN 2055-0294

Background: Fluoroquinolone (FQ) antimicrobials have antipyretic effects during the treatment of bacterial infections; however, it is not clear whether these are due to their antimicrobial activities or their hypothermic effects. In this study, we investigated the hypothermic effects of FQ antimicrobials (ciprofloxacin [CPFX], gatifloxacin [GFLX], and levofloxacin [LVFX]) on fever by evaluating rectal body temperature changes in a mouse model of non-bacterial fever. Methods: CPFX, GFLX, and LVFX were administered intraperitoneally to non-bacterial fever model mice induced by yeast. Rectal body temperature was measured up to 180 min after administration. Results: A decrease in rectal body temperature of up to 1.2 °C for CPFX, 3.4 °C for GFLX, and 1.0 °C for LVFX was observed. The decrease in temperature was induced by an increase in the plasma concentration of FQ antimicrobials, suggesting that they are responsible for the temperature reduction. Focusing on glucocorticoids, one thermoregulation mechanism, we investigated the substances responsible for the reduction in rectal body temperature induced by FQ antimicrobials. Aminoglutethimide (an inhibitor of glucocorticoid production) were premedicated, followed by intraperitoneal administration of GFLX in the yeast-induced fever mouse model, resulting in attenuated GFLX-induced hypothermic effects. Conclusions: These results suggest that certain antipyretic effects of CPFX, GFPX, and LVFX during fever may contribute to their hypothermic effects; certain mechanisms are glucocorticoid-mediated.

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Optimal Teicoplanin Trough Concentration With Therapeutic Drug Monitoring in Children: A Systematic Review and Meta-analysis.

Hanai Y, Oda K, Ueda T, Matsumoto K, Murakami L, Uekusa S, Ohashi H, Nishimura K, Takesue Y, Matsuo K

Therapeutic drug monitoring 46 ( 6 ) 699 - 709 2024.07

Joint Work, ISSN 0163-4356

Background: Teicoplanin is used to treat serious Gram-positive bacterial infections. However, the optimal trough concentrations for pediatric patients remain unclear owing to the lack of monitoring guidelines. This study aimed to determine the optimal teicoplanin trough concentration for treating Gram-positive bacterial infections in children. Methods: A systematic review was conducted using 4 databases. Stepwise cutoffs within the range of 10–30 mcg/mL were used for efficacy and safety. Studies were included if they reported treatment success rates and/or all-cause mortality, nephrotoxicity, hepatotoxicity, and thrombocytopenia according to the trough concentration. Results: The meta-analysis included 12 studies involving 830 pediatric patients. Teicoplanin cutoff values of 10, 15, 20, and 30 mcg/mL were reported in 9, 8, 9, and 2 studies, respectively. Trough concentrations,10 mcg/mL significantly reduced the treatment success rate, with an odds ratio of 0.07 and a 95% confidence interval ranging from 0.01 to 0.40. The overall treatment success rate was 50.0% versus 95.7% observed at concentrations $10 mcg/mL. However, no significant difference was observed at the 15-, 20-, and 30-mcg/mL cutoffs, when compared with lower concentrations. Trough concentrations,20 mcg/mL were associated with a decreased risk of nephrotoxicity (odds ratio = 0.21; 95% confidence interval, 0.08–0.55). However, hepatotoxicity and thrombocytopenia showed no significant associations with trough concentration ranges between 10 and 30 mcg/mL. Conclusions: Although further prospective studies are required for validation, the authors’ findings suggest that 10- to 20-mcg/mL teicoplanin is the optimal trough concentration for enhanced clinical success and reduced toxicity in pediatric patients.

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Anti-edematous effects of epinastine, cetirizine and its enantiomers in λ-carrageenan-induced edema in rat hind paw

Taguchi K., Chuang V.T.G., Ozawa M., Sakamoto Y., Hara R., Iketani O., Enoki Y., Kizu J., Hori S., Matsumoto K.

Pharmazie (Pharmazie) 79 ( 6 ) 98 - 100 2024.06

Joint Work, ISSN 00317144

Urticaria is induced by the histamine released from mast cells which develops wheals (edema) as a visual feature. In clinical practice, second-generation histamine H1-receptor blockers are routinely used as the first-line symptomatic treatment for urticaria. Nevertheless, not much research has directly examined the second-generation histamine H1-receptor blockers’ ability to reduce edema. In this study, we directly evaluated the anti-edematous activities of three second-generation histamine H1-receptor blockers available in the market (epinastine hydrochloride, cetirizine hydrochloride, and levocetirizine hydrochloride) using a λ-carrageenan-induced footpad edema model. One hour before the induction of edema with 1% λ-carrageenan injection, all second-generation histamine H1-receptor blockers (5, 10, 50 and 100 mg/kg) were subcutaneously administered to rats. At 0.5 and 3 hours after λ-carrageenan administration, the edema volume was evaluated using a Plethysmometer. Epinastine hydrochloride significantly suppressed the edema growth in a dose-dependent manner. Cetirizine hydrochloride showed a slight anti-edematous effect, while levocetirizine significantly inhibited the development of edema in a dose-dependent manner. On the other hand, dextrocetirizine did not prevent edema from growing. In summary, second-generation histamine H1-receptor blockers, at least those examined in this study, may be able to reduce the clinical symptoms of urticaria associated with edema. Levocetirizine hydrochloride is also anticipated to have stronger anti-edematous effects than cetirizine hydrochloride because levocetirizine is responsible for cetirizine’s anti-edematous activity.

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Relationship between nephrotoxicity and area under the concentration-time curve of vancomycin in critically ill patients: a multicenter retrospective study.

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, Nagumoi F, Komatsu T, Tomizawa A, Takuma A, Chiba H, Nishi Y, Enoki Y, Taguchi K, Suzuki A

Microbiology spectrum (Microbiology spectrum) 12 ( 7 ) e0373923 2024.05

Joint Work

We aimed to assess the frequency of acute kidney injury (AKI) in different areas under the concentration-time curve (AUC) values of vancomycin (VAN) using a two-point blood collection method, allowing for accurate AUC assessment in critically ill patients. This multicenter retrospective observational study was conducted in eight hospitals. We retrospectively analyzed the data of patients who had received VAN in an intensive care unit (ICU) between January 2020 and December 2022. The primary outcome was the incidence of AKI. Patients were classified into three groups according to the AUC24-48h at the initial therapeutic drug monitoring (TDM) as follows: <500, 500-600, and ≥600 µg·h/mL. The AUC24-48h values were calculated using the Bayesian estimation software Practical AUC-guided TDM. Among 146 patients [median age (interquartile range), 67 (56-78) years; 39% women], the AUC24-48h <500 µg·h/mL had an AKI rate of 6.5% (7/107), the AUC24-48h 500-600 µg·h/mL had an AKI rate of 28.0% (7/25), and the AUC24-48h ≥600 µg·h/mL had an AKI rate of 42.9% (6/14). In multivariate Cox proportional hazard analysis, the AUC24-48h 500-600 µg·h/mL [hazard ratio 5.4, 95% confidence interval (CI) 1.64-17.63] and the AUC24-48h ≥600 μg·h/mL (hazard ratio 7.0, 95% CI 2.31-21.18) significantly correlated with a higher incidence of AKI compared with the AUC24-48h <500 μg·h/mL. In conclusion, we identified an association between AUC on day 2 and the risk of AKI in ICU patients, suggesting that not only AUCs above 600 µg·h/mL but also those between 500 and 600 µg·h/mL pose a risk for AKI. IMPORTANCE: Vancomycin (VAN) is a glycopeptide antibiotic and one of the most commonly used antibiotics for severe infections caused by methicillin-resistant Staphylococcus aureus. However, higher VAN concentrations have been associated with an increased risk of acute kidney injury (AKI). Herein, we aimed to assess the frequency of AKI in different areas under the concentration-time curve (AUC) values of VAN using a two-point blood collection method, allowing for accurate AUC assessment in critically ill patients. We identified an association between AUC on day 2 and the risk of AKI in intensive care unit patients, suggesting that not only AUCs above 600 µg·h/mL but also those between 500 and 600 µg·h/mL pose a risk for AKI. Therefore, individualized dosing is feasible, with pharmacists being able to optimize VAN doses to attain appropriate targets.

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Direct comparison of anti-inflammatory effects of 14-, 15-, and 16-membered macrolide antibiotics in experimental inflammation model induced by carrageenan in rats.

Taguchi K, Chuang VTG, Ogino H, Hara R, Iketani O, Enoki Y, Kizu J, Hori S, Matsumoto K

Die Pharmazie (Pharmazie) 79 ( 3 ) 64 - 66 2024.05

Joint Work, ISSN 0031-7144

Some macrolide antibiotics, which share a basic lactone ring structure, also exhibit anti-inflammatory actions in addition to their antibacterial activities. However, no study has directly compared anti-inflammatory effects on acute inflammation among macrolide antibiotics with the distinct size of the lactone ring. In this study, we evaluated and compared the anti-inflammatory activities of four 14-membered macrolides (erythromycin, clarithromycin, roxithromycin, oleandomycin), one 15-membered macrolide (azithromycin), and three 16-membered macrolides (midecamycin, josamycin, leucomycin) using a rat carrageenan-induced footpad edema model. All macrolide antibiotics were intraperitoneally administered to rats one hour before the induction of inflammatory edema with 1% λ-carrageenan. The anti-inflammatory effects on acute inflammation were evaluated by changing the edema volume. All 14-membered and 15-membered macrolide antibiotics significantly suppressed the development of edema. Conversely, none of the 16-membered macrolide antibiotics inhibited the growth of edema. In conclusion, compared to 16-membered macrolide antibiotics, 14-membered and 15-membered macrolide antibiotics have stronger anti-inflammatory effects. Further research should be done to determine why different lactone ring sizes should have distinct anti-inflammatory effects.

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