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

Pharmaceutical research 41 ( 11 ) 2161 - 2171 2024.11

ISSN 0724-8741

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Predictive Value of Vancomycin AUC<inf>24</inf>/MIC Ratio for 30-day Mortality in Patients with Severe or Complicated Methicillin-Resistant Staphylococcus aureus Infections: A Multicenter Retrospective Study

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

Pharmaceutical Research 41 ( 7 ) 1381 - 1389 2024.07

ISSN 07248741

Background: Although vancomycin is typically employed against methicillin-resistant Staphylococcus aureus (MRSA) infections, the optimal ratio of 24-h area under the concentration–time curve to minimum inhibitory concentration (AUC24/MIC) for severe or complicated infections lacks clear guideline recommendations. This study aimed to determine the target AUC24/MIC ratio associated with treatment outcomes of infections treated with vancomycin. Methods: This retrospective multicenter cohort study included adult patients receiving ≥ 5 days of vancomycin for severe/complicated MRSA infections (e.g., osteoarticular, pulmonary, endocarditis, etc.) between January 2018 and December 2023. The primary outcome was 30-day mortality, with secondary outcomes including clinical success, microbiological eradication, and nephrotoxicity. Receiver operating characteristic (ROC) curve analysis was used to identify the AUC24/MIC cutoff for 30-day mortality. Multivariate regression analysis was used to determine association between AUC24/MIC and outcomes. Results: This study included 82 patients. ROC identified a target AUC24/MIC of ≥ 505 for 30-day mortality. The overall 30-day mortality rate (22.0%) was significantly higher for below average AUC24/MIC cutoff (34.1%) than for above AUC24/MIC cutoff group (9.8%). Multivariate analysis confirmed AUC24/MIC of < 505 as an independent predictor (adjusted odds ratio, 5.001; 95% confidence interval, 1.335–18.75). The clinical success rate differed significantly between below- and above-cutoff groups, whereas microbiological eradication tended to favor the above-cutoff group. The nephrotoxicity rates were comparable between groups. Conclusions: In treating severe/complicated MRSA infections, vancomycin AUC24/MIC ratio ≥ 505 was independently associated with favorable 30-day mortality. Given the retrospective nature of this study, further prospective studies are essential to confirm the reliability of the target AUC24/MIC ratios.

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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 (American Society for Microbiology) 12 ( 7 ) e0373923 2024.07

ISSN 2165-0497

We aimed to assess the frequency of acute kidney injury (AKI) in differentareas 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 classifiedinto 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% confidenceinterval (CI) 1.64-17.63] and the AUC24-48h ≥600 μg h/mL (hazard ratio 7.0, 95% CI 2.31-21.18) significantlycorrelated with a higher incidence of AKI compared with the AUC24-48h <500 μg h/mL. In conclusion, we identifiedan 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.

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 79 ( 6 ) 98 - 100 2024.06

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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Dual delivery of carbon monoxide and doxorubicin using haemoglobin-albumin cluster: proof of concept for well-tolerated cancer therapy

Ito C., Taguchi K., Yamada T., Hanaya K., Enoki Y., Sugai T., Komatsu T., Matsumoto K.

Journal of Materials Chemistry B 12 ( 23 ) 5600 - 5608 2024.05

ISSN 2050750X

A serious concern of doxorubicin (DOX) therapy is that it causes severe adverse effects, particularly cardiotoxicity. Carbon monoxide (CO) possesses powerful cytoprotective effects against drug-induced organ injury and is expected to ameliorate DOX-induced cardiotoxicity. In this study, a dual carrier of DOX and CO (CO-HemoAct-DOX) was fabricated based on a haemoglobin-albumin cluster (HemoAct), which is a protein cluster with a haemoglobin core structure wrapped by serum albumin. CO-HemoAct-DOX was synthesised by binding CO to a haemoglobin core and covalently conjugating (6-maleimidocaproyl)hydrazone derivative of DOX to an albumin shell. The average DOX/cluster ratio was about 2.6. In the in vitro cytotoxicity assay against cancer cells, the anti-tumour activity of CO-HemoAct-DOX was 10-fold lower than that of DOX in a 2D-cultured model, whereas CO-HemoAct-DOX suppressed the growth of tumour spheroids to the same extent as DOX in the 3D-cultured model. In colon-26 tumour-bearing mice, CO-HemoAct-DOX achieved DOX delivery to the tumour site and alleviated tumour growth more effectively than DOX. Furthermore, CO-HemoAct attenuated DOX-induced cardiomyocyte atrophy in H9c2 cells and elevated the levels of cardiac biomarkers in mice exposed to DOX. These results suggest that the dual delivery of CO and DOX using HemoAct is a promising strategy as an anti-tumour agent to realise well-tolerated cancer therapy with minimal cardiotoxicity.

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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 V.T.G., Ogino H., Hara R., Iketani O., Enoki Y., Kizu J., Hori S., Matsumoto K.

Pharmazie 79 ( 3-5 ) 64 - 66 2024.05

ISSN 00317144

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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Flowchart for predicting achieving the target area under the concentration-time curve of vancomycin in critically ill Japanese patients: A multicenter retrospective study

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

Journal of Infection and Chemotherapy 30 ( 4 ) 329 - 336 2024.04

ISSN 1341321X

Introduction: In therapeutic drug monitoring (TDM) of vancomycin (VCM), the area under the concentration-time curve (AUC) is related to the clinical efficacy and toxicity. Therefore, herein, we examined the factors associated with achieving the target AUC at follow-up and developed a decision flowchart for achieving the target AUC in critically ill patients. Methods: This multicenter retrospective observational study was conducted at eight hospitals. We retrospectively analyzed data from patients who had received VCM in the intensive care unit from January 2020 to December 2022. Decision-tree (DT) analysis was performed using factors with p < 0.1 in univariate analysis as the independent variables. Case data were split up to two times, and four subgroups were included. The primary endpoint was achieving the target AUC at the follow-up TDM (AUCfollow-up) and target AUCfollow-up achievement was defined as an AUC of 400–600 μg‧h/mL. The initial AUC values were calculated with the 2-point concentrations (peak and trough) using the Bayesian estimation software Practical AUC-guided TDM (PAT). Results: Among 70 patients (median age [interquartile range], 66 [56, 79] years; 50 % women), the AUCfollow-up was achieved in 70 % (49/70). Three factors were selected for the decision flow chart: predicted AUCfollow-up of 400–600 μg‧h/mL, dosing at 12-h intervals, and CCr of 130 mL/min/1.73 m2 or higher; the accuracy was adequate (92 %, R2 0.52). Conclusion: We successfully identified the factors associated with achieving the target AUC of VCM at follow-up TDM and developed a simple-to-use DT model. However, the validity of the findings needs to be evaluated.

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同種造血幹細胞移植後にポサコナゾール腸溶錠の血中濃度が低値を示した一例

島村千陽, 坂本靖宜, 長谷川拓也, 榎木裕紀, 田口和明, 松元一明

日本化学療法学会雑誌 ((公社)日本化学療法学会) 72 ( 1 ) 116 - 116 2024.01

ISSN 1340-7007

T-cell immunosuppression in sepsis is augmented by sciatic denervation-induced skeletal muscle atrophy

Osa S., Enoki Y., Takahashi D., Chuang V.T.G., Taguchi K., Matsumoto K.

FEBS Letters 598 ( 20 ) 2581 - 2591 2024

Accepted, ISSN 00145793

Skeletal muscle atrophy is a known risk factor for immunosuppressive conditions and for a poor prognosis in sepsis. However, its immunopathology has not been experimentally elucidated. This study investigated the effects of skeletal muscle atrophy on the immunopathology of sepsis. Male C57BL/6J mice were subjected to sciatic denervation (DN) and caecal ligation and puncture (CLP) to induce muscle atrophy or sepsis. The macrophages, myeloid-derived suppressor cells (MDSC), and T-cells in peritoneal and spleen were analysed using flow cytometry. DN-induced muscle atrophy did not affect macrophage and MDSC populations. In contrast, the percentage of cytotoxic T-lymphocyte-associated antigen (CTLA)-4+ CD4+ T-cells, programmed death (PD)-1+ CD8+ T-cells, regulatory T-cells, and the CTLA-4+ regulatory T-cells was statistically significantly higher in DN-CLP mice than in sham-CLP mice. Skeletal muscle atrophy before sepsis triggers excessive T cell immunosuppression, which may contribute to the exacerbation of sepsis under skeletal muscle atrophy.

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

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

Journal of Infection and Chemotherapy 31 ( 1 ) 102485 2024

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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Antimicrobial Stewardship of Oral Third-Generation Cephalosporins in Community Pharmacy: A Single-Center Quasi-Experimental Study

Nakamura Koyo, Matsumoto Kazuaki, Enoki Yuki, Taguchi Kazuaki, Yamashita Shuji, Kai Junko, Hayashi Hideki

Biological and Pharmaceutical Bulletin (The Pharmaceutical Society of Japan) 47 ( 8 ) 1447 - 1451 2024

ISSN 0918-6158

<p>Proper use of antimicrobials in hospital and outpatient settings is critical for minimizing the occurrence of antimicrobial resistance. Some hospitals have intervened in the inappropriate use of third-generation oral cephalosporins. However, there have been no such studies in community pharmacy settings. This study aimed to investigate how the use of oral third-generation cephalosporins in community pharmacies affects the amount of antimicrobials used. Patients who visited Nakanomaru Pharmacy after being prescribed antimicrobials at target medical institutions between February 2021 and January 2023 were identified. The number of oral antimicrobials used, duration of use, number of prescriptions, patient age and sex, and infectious diseases in the target patients before and after the intervention for the proper use of oral third-generation cephalosporins were retrospectively investigated based on the patients’ medication history and prescription receipts. Through efforts to ensure the proper use of oral third-generation cephalosporins, the amount of oral third-generation cephalosporins used has decreased, and the use of penicillins and oral first-generation cephalosporins has increased. There was no increase in the antimicrobial change or relapse rates associated with treatment failure before and after the initiation of appropriate antimicrobial use. By working toward the proper use of oral third-generation cephalosporins in community pharmacies, we were able to reduce the doses of oral third-generation cephalosporins without compromising their therapeutic efficacy. We believe that recommending the selection of narrow-spectrum antimicrobials based on these guidelines will contribute to their proper use.</p>

Elucidating the binding properties of methemoglobin in red blood cell to cyanide, hydrosulfide, and azide ions using artificial red blood cell

Yuto Suzuki, Yo Arakida, Hiromi Sakai, Yuki Enoki, Kazuaki Matsumoto, Kazuaki Taguchi

Toxicology and Applied Pharmacology (Elsevier BV) 481 116752 - 116752 2023.12

Accepted, ISSN 0041008X

Methemoglobin (metHb), the oxidized form of hemoglobin, lacks the ability of reversible oxygen binding; however, it has a high binding affinity to toxic substances such as cyanide, hydrosulfide, and azide. This innate property of metHb offers the clinical option to treat patients poisoned with these toxins, by oxidizing the endogenous hemoglobin in the red blood cells (RBCs). The binding properties of naked metHb (isolated from RBC) with these toxins has been studied; however, the binding behaviors of metHb under the intracellular conditions of RBC are unclear because of the difficulty in detecting metHb status changes in RBC. This study aimed to elucidate the binding properties of metHb in RBC under physiological and poisoned conditions using artificial RBC, which was hemoglobin encapsulated in a liposome. The mimic-circumstances of metHb in RBC (metHb-V) was prepared by oxidizing the hemoglobin in artificial RBC. Spectroscopic analysis indicated that the metHb in metHb-V exhibited a binding behavior different from that of naked metHb, depending on the toxic substance: When the pH decreased, (i) the cyanide binding affinity of metHb-V remained unchanged, but that of naked metHb decreased (ii) the hydrosulfide binding affinity was increased in metHb-V but was decreased in naked metHb. (iii) Azide binding was increased in metHb-V, which was similar to that in naked metHb, irrespective of the pH change. Thus, the binding behavior of intracellular metHb in the RBC with cyanide, hydrosulfide, and azide under physiological and pathological conditions were partly elucidated using the oxidized artificial RBC.

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Oral teicoplanin administration suppresses recurrence of Clostridioides difficile infection: Proof of concept

Tanaka Y., Tashiro S., Ikegami S., Enoki Y., Taguchi K., Matsumoto K.

Anaerobe 84 102789 2023.12

ISSN 10759964

Objectives: Teicoplanin is a potential antimicrobial candidate for Clostridioides difficile infection (CDI) treatment. However, the therapeutic potential of teicoplanin against severe CDI has not been clinically proven. In the present study, we investigated the efficacy of oral teicoplanin administration against severe CDI and the recurrence of severe CDI after teicoplanin treatment in a mouse model. Methods: A lethal CDI mouse model was established by colonizing the mice with C. difficile ATCC® 43255; they were orally administered teicoplanin (128 mg/kg/d) or vancomycin (160 mg/kg/d) for 10 d, 24 h after C. difficile spore challenge, and physiological and biological responses were monitored for 20 d after the initial antibiotic treatment. We also performed the in vitro time-kill assay and determined minimum inhibitory concentration (MIC), post-antibiotic effect, and toxin production with antibiotic exposure. Results: The therapeutic response (survival rates, body weight change, clinical sickness score grading, C. difficile load, and toxin titer in feces) of oral teicoplanin administration was comparable to that of oral vancomycin administration in the lethal CDI mouse model. Moreover, teicoplanin treatment suppressed the re-onset of diarrhea and re-increase in toxin titer 10 d after treatment compared with that by vancomycin treatment. In in vitro experiments, teicoplanin exhibited time-dependent antibacterial activity and possessed lower MIC and longer post-antibiotic effect than vancomycin against C. difficile. C. difficile toxin production was numerically lower with teicoplanin exposure than with vancomycin exposure. Conclusions: The results obtained from the present basic experiments could suggest that teicoplanin is a potential antibiotic for the treatment of severe CDI with recurrence-prevention activity.

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The anti-inflammatory effect of tedizolid on carrageenan-induced footpad edema rat model

Isobe N., Chuang V.T.G., Liu X., Enoki Y., Taguchi K., Matsumoto K.

Journal of Infection and Chemotherapy 29 ( 11 ) 1088 - 1090 2023.11

ISSN 1341321X

Tedizolid (TZD) is an oxazolidinone anti-methicillin-resistant Staphylococcus aureus (MRSA) drug. Linezolid (LZD), another oxazolidinone, has been shown to have an anti-inflammatory effect. TZD has been shown to exhibit an anti-inflammatory effect in a murine model of hematogenous pulmonary infection. In this study, we further investigated the anti-inflammatory effect of TZDs using a carrageenan-induced rat footpad edema model. TZD was administered at 0, 10, 20, and 40 mg/kg to the carrageenan-induced rat footpad edema model, and the edema rate was measured over time up to 9 h later. The area under the time curve of the edema rate profile (AUCedema0→9) decreased in a TZD dose-dependent manner. In addition, the correlation between AUCedema0→9 and the area under the time curve of free TZD plasma concentration (fAUCblood) obtained from the pharmacokinetic study of TZD in the carrageenan-induced rat footpad edema model was examined. fAUCblood and AUCedema0→9 showed a good negative correlation. These results indicate that TZD suppresses carrageenan-induced footpad edema and that TZD exerts its anti-inflammatory effects in a plasma concentration-dependent manner.

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Pharmaceutical stability of methemoglobin-albumin cluster as an antidote for hydrogen sulfide poisoning after one-year storage in freeze-dried form

Suzuki Y., Taguchi K., Okamoto W., Enoki Y., Komatsu T., Matsumoto K.

International Journal of Pharmaceutics 645 123433 2023.10

ISSN 03785173

Long-term stability during storage is an important requirement for pharmaceutical preparations. The methemoglobin (metHb)-albumin cluster, in which bovine metHb is covalently enveloped with an average of three human albumin molecules, is a promising antidote for hydrogen sulfide (H2S) poisoning. In this study, we investigated the pharmaceutical stability of metHb-albumin cluster after storage for one year in solution and as freeze-dried powder. The lyophilized powder of metHb-albumin cluster stored for one year was readily reconstituted in sterile water for injection, yielding a homogeneous brown solution. Physicochemical measurements revealed that the overall structure of the metHb-albumin cluster was still maintained after preservation. Results of the pharmacological study showed that 100 % of the H2S-poisoned mice survived after treatment with the reconstituted solution of metHb-albumin cluster powder. Furthermore, the solution did not cause any toxic reactions. The antidotal efficacy of metHb-albumin cluster for H2S poisoning was preserved in freeze-dried powder form for at least one year.

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