研究者詳細 - 松元　一明

論文 - 松元　一明

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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 （Anaerobe） 84 102789 2023年10月

共著, ISSN 1075-9964

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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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 （International Journal of Pharmaceutics） 645 123433 2023年10月

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

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

Pharmaceutical research （Pharmaceutical Research） 40 （ 10 ） 2423 - 2431 2023年10月

共著, ISSN 0724-8741

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

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Ceftriaxone-Related Encephalopathy in a Patient With End-Stage Renal Disease and High Ceftriaxone Concentrations in Cerebrospinal Fluid and Plasma: A Case Report.

Takano T, Kaburagi M, Morikubo S, Ichikawa D, Matsumoto K

Cureus 15 （ 10 ） e46401 2023年10月

共著, ISSN 2168-8184

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Model-informed precision dosing of vancomycin for rapid achievement of target area under the concentration-time curve: A simulation study.

Oda K, Yamada T, Matsumoto K, Hanai Y, Ueda T, Samura M, Shigemi A, Jono H, Saito H, Kimura T

Clinical and translational science （Clinical and Translational Science） 16 （ 11 ） 2265 - 2275 2023年09月

共著, ISSN 1752-8054

In this study, we aimed to evaluate limited sampling strategies for achieving the therapeutic ranges of the area under the concentration-time curve (AUC) of vancomycin on the first and second day (AUC0–24, AUC24–48, respectively) of therapy. A virtual population of 1000 individuals was created using a population pharmacokinetic (PopPK) model, which was validated and incorporated into our model-informed precision dosing tool. The results were evaluated using six additional PopPK models selected based on a study design of prospective or retrospective data collection with sufficient concentrations. Bayesian forecasting was performed to evaluate the probability of achieving the therapeutic range of AUC, defined as a ratio of estimated/reference AUC within 0.8–1.2. The Bayesian posterior probability of achieving the AUC24–48 range increased from 51.3% (a priori probability) to 77.5% after using two-point sampling at the trough and peak on the first day. Sampling on the first day also yielded a higher Bayesian posterior probability (86.1%) of achieving the AUC0–24 range compared to the a priori probability of 60.1%. The Bayesian posterior probability of achieving the AUC at steady-state (AUCSS) range by sampling on the first or second day decreased with decreased kidney function. We demonstrated that second-day trough and peak sampling provided accurate AUC24–48, and first-day sampling may assist in rapidly achieving therapeutic AUC24–48, although the AUCSS should be re-estimated in patients with reduced kidney function owing to its unreliable predictive performance.

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A combination of 5/6-nephrectomy and unilateral ureteral obstruction model accelerates progression of remote organ fibrosis in chronic kidney disease

Homma Kyoka, Enoki Yuki, Uchida Sato, Taguchi Kazuaki, Matsumoto Kazuaki

FASEB BIOADVANCES （FASEB BioAdvances） 5 （ 10 ） 377 - 394 2023年08月

共著

Chronic kidney disease (CKD) involves progressive renal fibrosis, which gradually reduces kidney function and often causes various complications in extrarenal tissues. Therefore, we investigated fibrogenesis in extrarenal tissues (heart, liver, and lungs) in different experimental CKD models, such as the 5/6-nephrectomy (5/6 Nx), unilateral ureteral obstruction (UUO), and a combination (2/3 Nx + UUO). We evaluated the degree of fibrogenesis in kidneys and extrarenal tissues by histological analysis and quantification of fibrosis-related gene and protein expression. To elucidate the fibrosis mechanisms observed in 2/3 Nx + UUO mice, we evaluated the effect of indoxyl sulfate (IS), a typical uremic toxin accumulated in CKD, and transforming growth factor-β (TGF-β), a fibrosis-related factor, on fibrosis using human hepatoma (HepG2) and RAW264.7 cells. A significant decline in renal function was observed in the 5/6 Nx and 2/3 Nx + UUO models, whereas a significant increase in renal fibrosis was observed only in the obstructed kidneys. Notable amount of fibrosis was induced in the liver and heart in the 2/3 Nx + UUO model, with the induction of macrophage infiltration and increased tissue IS and TGF-β levels. In agreement with the results of in vivo experiments, co-stimulation with IS, TGF-β, and macrophage-conditioned medium increased the expression of fibrogenic genes in HepG2 cells. We demonstrated that the 2/3 Nx + UUO model induced both loss of renal function and renal fibrosis in the earlier stages, providing a novel CKD model that induces remote organ fibrosis in a shorter time.

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Polysarcosine-Coated liposomes attenuating immune response induction and prolonging blood circulation.

Hu M, Taguchi K, Matsumoto K, Kobatake E, Ito Y, Ueda M

Journal of colloid and interface science （Journal of Colloid and Interface Science） 651 273 - 283 2023年07月

共著, ISSN 0021-9797

Hypothesis: Liposomes coated with long polysarcosine (PSar) chains at a high density might enable long blood circulation and attenuate accelerated blood clearance (ABC) phenomenon. Experiments: In this study, we controlled the length (23, 45, 68 mers) and density (5, 10, 15 mol%) of PSar on liposomal coatings and, furthermore, investigated the effects of PSar length and density on the blood circulation time, biodistribution, immune response, and ABC phenomenon induction. Length-controlled PSar-bound lipids (PSar-PEs) were synthesized using a click reaction and inserted into bare liposomes at different combinations of chain lengths and proportions. Findings: Although all PSar-coated liposomes (PSar-lipos) had similar morphological, physical, and chemical properties, they had different blood circulation times and biodistribution, and exerted varied effects on the immune system. All PSar-lipos with different PSar length and density showed a similar anti-PSar IgM response. Liposomes modified with the longest PSar chain (68 mers) at a high density (15 mol%) showed the longest blood circulation time and, additionally, attenuated ABC phenomenon compared with PEG-lipo. The ex vivo analysis of the biodistribution of liposomes revealed that a thick PSar layer enhanced the blood circulation time of liposomes due to the reduction of the accumulation of liposomes in the liver and spleen. These findings provide new insights into the relationship between IgM expression and ABC phenomenon inhibition.

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

Isobe N, Chuang VTG, Liu X, Enoki Y, Taguchi K, Matsumoto K

Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy （Journal of Infection and Chemotherapy） 29 （ 11 ） 1088 - 1090 2023年07月

共著, ISSN 1341-321X

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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Anti-Inflammatory Actions of Expectorants in a Rat Carrageenan-Induced Footpad Edema Model.

Ito M, Liu X, Taguchi K, Enoki Y, Kuroda Y, Kizu J, Matsumoto K

Die Pharmazie （Pharmazie） 78 （ 6 ） 86 - 88 2023年07月

共著, ISSN 0031-7144

S-Carboxymethyl-L-cysteine (SCMS) exhibits sputum-regulating and anti-inflammatory actions. Previous studies reported the anti-inflammatory effects of SCMS on chronic inflammatory diseases, but no study has examined these effects on acute inflammatory diseases. In this study, we investigated the anti-inflammatory effects of SCMS in a rat carrageenan-induced footpad edema model, which is routinely used as an acute inflammation model. Expectorants were administered to rats with footpad edema induced by subcutaneously administering 1% λ-carrageenan to the footpad of the left posterior limb, and the dose dependency of the anti-inflammatory effects was evaluated. As a result, even when the dose of SCMS was increased to 400 mg/kg, there were no inhibitory effects on edema. Furthermore, we examined the inhibitory effects of other expectorants (ambroxol hydrochloride, N-acetyl-L-cysteine, L-cysteine ethylester hydrochloride, and L-cysteine methylester hydrochloride), which were reported to exhibit anti-inflammatory effects on chronic inflammation, on edema. However, none of these expectorants inhibited edema.

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Pharmaceutical Integrity of Lyophilized Methemoglobin-Albumin Clusters after Reconstitution

Suzuki Yuto, Taguchi Kazuaki, Okamoto Wataru, Enoki Yuki, Komatsu Teruyuki, Matsumoto Kazuaki

ACS OMEGA （ACS Omega） 8 （ 25 ） 22589 - 22595 2023年06月

共著, ISSN 2470-1343

Covalent attachment of a ferric hemoglobin (metHb) core to three human serum albumin molecules to form metHb-albumin clusters has previously been used to develop an antidote for hydrogen sulfide poisoning. Lyophilization is one of the most effective approaches to preserve protein pharmaceuticals with minimum contamination and decomposition. However, there is concern that lyophilized proteins may undergo pharmaceutical alteration on reconstitution. This study investigated the pharmaceutical integrity of metHb-albumin clusters on lyophilization and reconstitution with three clinically available reconstitution fluids, (i) sterile water for injection, (ii) 0.9% sodium chloride injection, and (iii) 5% dextrose injection. The metHb-albumin clusters retained their physicochemical properties and structural integrity on lyophilization and reconstitution with sterile water for injection or 0.9% sodium chloride injection, along with comparable hydrogen sulfide scavenging ability compared to non-lyophilized metHb-albumin clusters. The reconstituted protein completely rescued lethal hydrogen sulfide poisoning in mice. On the other hand, lyophilized metHb-albumin clusters reconstituted with 5% dextrose injection showed physicochemical changes and a higher mortality rate in mice subjected to lethal hydrogen sulfide poisoning. In conclusion, lyophilization represents a potent preservation method for metHb-albumin clusters if either sterile water for injection or 0.9% sodium chloride injection is used for reconstitution.

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Polyoxazoline-conjugated porcine serum albumin as an artificial plasma expander for dogs.

Okamoto W, Usui T, Hasegawa M, Kobayashi T, Fujisawa J, Taguchi K, Matsumoto K, Kohno M, Iwazaki M, Shimano S, Nagao I, Toyoda H, Matsumura N, Tomiyasu H, Tochinai R, Komatsu T.

Scientific Reports （Scientific Reports） 13 （ 1 ） 9512 2023年06月

共著, ISSN 2045-2322

Veterinary medicine has made tremendous progress for domestic dogs, which are irreplaceable family members enriching human life. Nevertheless, no adequate supply system exists for their blood products. This study examined the synthesis, structure, safety, and efficacy of poly(2-ethyl-2-oxazoline)-conjugated porcine serum albumin (POx-PSA) as an artificial plasma expander for dogs. The aqueous POx-PSA solution showed moderately high colloid osmotic pressure and good blood cell compatibility. Actually, lyophilized powder stored for 1 year can regenerate into a homogeneous solution. The circulation half-life of POx-PSA in rats was 2.1-fold longer than that of naked PSA. Rats produced neither anti-PSA IgG antibody nor anti-POx IgG antibody, which suggests excellent immunological stealth properties of POx-PSA. Complete resuscitation of hemorrhagic shock in rats was achieved soon after injection of POx-PSA solution. Serum biochemistry tests and histopathological observations indicated no abnormality in the related organs. When POx-PSA was administered to dogs intravenously, (i) no serum biochemical or hematological alteration was observed, also (ii) no overt deterioration of animal health was observed. These results indicate that POx-PSA has potential as an artificial plasma expander for dogs.

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In vivo Pharmacokinetics/Pharmacodynamics Profiles for Appropriate Doses of Cefditoren pivoxil against S. pneumoniae in Murine Lung-Infection Model.

Igarashi Y, Kojima N, Takemura W, Liu X, Morita T, Mizukami Y, Enoki Y, Taguchi K, Yokoyama Y, Nakamura T, Matsumoto K

Pharmaceutical research 2023年05月

共著, ISSN 0724-8741

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Antimicrobial Efficacy Evaluations of Metronidazole against Clostridioides difficile Infection using Fecal Pharmacokinetic and Pharmacodynamic Analyses.

Tashiro S, Taguchi K, Enoki Y, Matsumoto K

Pharmaceutical research （Pharmaceutical Research） 40 （ 7 ） 1799 - 1806 2023年05月

共著, ISSN 0724-8741

Objectives: The pharmacokinetics/pharmacodynamics (PK/PD) characteristics of metronidazole (MNZ) in Clostridioides difficile infection (CDI) remain unclear. We aimed to determine the PK/PD characteristics of MNZ using a fecal PK/PD analysis model. Methods: Susceptibility testing, time-kill studies, and post-antibiotic effect (PAE) measurements were performed to evaluate in vitro PD profiles. MNZ was subcutaneously administered to mice infected with C. difficile ATCC® 43255 to evaluate in vivo PK and PD profiles, followed by determining fecal PK/PD indices with target value. Results: MNZ exerted concentration-dependent bactericidal activities with minimum inhibitory concentration (MIC) and PAE being 0.79 µg/mL and 4.8 h, respectively, against C. difficile ATCC® 43255. The reduction in vegetative cells in feces and treatment outcomes were most closely correlated with the ratio of the area under the fecal drug concentration–time curve from 0 to 24 h to the MIC (fecal AUC24/MIC). The target value of fecal AUC24/MIC to achieve a 1 log10 reduction in vegetative cells was 188. Upon meeting the target value, high survival rates (94.5%) and low clinical sickness score grading (5.2) were achieved in the CDI mouse models. Conclusions: The PK/PD index and its target value of MNZ for CDI treatment was fecal AUC24/MIC ≥ 188. These findings may contribute to the effective clinical use of MNZ.

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Methemoglobin-albumin clusters for cyanide detoxification

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

Toxicology and Applied Pharmacology （Toxicology and Applied Pharmacology） 466 116472 2023年05月

共著, ISSN 0041008X

Sodium nitrite (NaNO2) is a universal antidote for patients with cyanide poisoning. However, its use has serious drawbacks in terms of efficacy and safety. Herein, we present a promising antidote: methemoglobin (metHb)-albumin clusters. The metHb-albumin cluster is made by a metHb core wrapped by covalently bound human serum albumin. Spectral analyses proved that the metHb-albumin clusters possessed cyanide-binding properties similar to those of naked metHb. In vitro cell experiments showed that metHb-albumin clusters prevented the cyanide-induced inhibition of cytochrome c oxidase activity, resulting in a strong cytoprotective effect. In mice subjected to cyanide poisoning, metHb-albumin clusters reduced mortality and alleviated metabolic acidosis, while maintaining the activity of cytochrome c oxidase in organs; their efficacy was better than that of NaNO2. Furthermore, the oxygen carrying capacity was maintained in poisoned mice treated with metHb-albumin clusters and was low in those treated with NaNO2. These results indicate that metHb-albumin clusters could be a more effective and safer antidote against cyanide poisoning than NaNO2.

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Optimal therapeutic recommendation for Clostridioides difficile infection in pediatric and adolescent populations: a systematic review and meta-analysis.

Tashiro S, Mihara T, Okawa R, Tanaka Y, Samura M, Enoki Y, Taguchi K, Matsumoto K, Yamagishi Y

European journal of pediatrics （European Journal of Pediatrics） 182 （ 6 ） 2673 - 2681 2023年03月

共著, ISSN 0340-6199

We conducted a systematic review and meta-analysis to examine the efficacy profiles of metronidazole (MNZ) and vancomycin (VCM) in pediatric and adolescent patients with Clostridioides difficile infection (CDI). A systematic review and meta-analysis was conducted using four electronic databases (PubMed, Cochrane Library, Web of Science, and Clinicaltrials.gov) through July 6, 2022. We analyzed the clinical cure and recurrence rates to determine the efficacy of MNZ and VCM. The clinical cure rates in all included studies were not significantly different between MNZ and VCM (OR = 0.63; 95% CI = 0.36–1.10; I2 = 0%; P = 0.10). Subgroup analyses were performed separately for each region to account for regional differences in the CDI. MNZ treatment achieved significantly lower clinical cure rates than did VCM in the United States of America (USA) and Europe (OR = 0.42, 95% CI = 0.19–0.93, I2 = 0%, P = 0.03). Recurrence rates were not significantly different between MNZ and VCM (OR = 1.48, 95% CI = 0.62–3.53, I2 = 28%, P = 0.38). Conclusion: MNZ exhibited significantly lower clinical cure rates than did VCM in the US and Europe; therefore, it is not recommended for the management of CDI in pediatric and adolescent populations.What is Known:• The unavailability of robust data on recommendations of therapeutic agents for the management of Clostridioides difficile infections in children precludes effective antibiotic choice.What is New:• Metronidazole exhibited significantly lower clinical cure rates than did vancomycin in the United States of America and Europe and recurrence rate was not significantly different between metronidazole and vancomycin; therefore, it is not recommended for the management of Clostridioides difficile infection in children.

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

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

The Journal of antimicrobial chemotherapy （The Journal of antimicrobial chemotherapy） 78 （ 4 ） 991 - 999 2023年02月

共著, ISSN 0305-7453

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

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Model-informed precision dosing of teicoplanin for the rapid achievement of the target area under the concentration-time curve: A simulation study.

Oda K, Yamada T, Matsumoto K, Hanai Y, Ueda T, Samura M, Shigemi A, Jono H, Saito H, Kimura T

Clinical and translational science （Clinical and Translational Science） 16 （ 4 ） 704 - 713 2023年02月

共著, ISSN 1752-8054

Teicoplanin, a glycopeptide antimicrobial, is recommended for therapeutic drug monitoring, but it remains unclear how to target the area under the concentration-time curve (AUC). This simulation study purposed to demonstrate the potential of the Bayesian forecasting approach for the rapid achievement of the target AUC for teicoplanin. We generated concordant and discordant virtual populations against a Japanese population pharmacokinetic model. The predictive performance of the Bayesian posterior AUC in limited sampling on the first day against the reference AUC was evaluated as an acceptable target AUC ratio within the range of 0.8–1.2. In the concordant population, the probability for the maximum a priori or Bayesian posterior AUC on the first day (AUC0–24) was 61.3% or more than 77.0%, respectively. The Bayesian posterior AUC on the second day (AUC24–48) was more than 75.1%. In the discordant population, the probability for the maximum a priori or Bayesian posterior AUC0–24 was 15.5% or 11.7–80.7%, respectively. The probability for the maximum a priori or Bayesian posterior AUC24–48 was 23.4%, 30.2–82.1%. The AUC at steady-state (AUCSS) was correlated with trough concentration at steady-state, with a coefficient of determination of 0.930; the coefficients on days 7 and 4 were 0.442 and 0.125, respectively. In conclusion, this study demonstrated that early sampling could improve the probability of AUC0–24 and AUC24–48 but did not adequately predict AUCSS. Further studies are necessary to apply early sampling-based model-informed precision dosing in the clinical settings.

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Comparison of the efficacy and safety of standard- and high-dose daptomycin: a systematic review and meta-analysis.

Samura M, Takada K, Hirose N, Kurata T, Nagumo F, Uchida M, Inoue J, Tanikawa K, Enoki Y, Taguchi K, Matsumoto K, Ueda T, Fujimura S, Mikamo H, Takesue Y, Mitsutake K

British journal of clinical pharmacology （British Journal of Clinical Pharmacology） 89 （ 4 ） 1291 - 1303 2023年01月

共著, ISSN 0306-5251

Aims: Standard doses of daptomycin at 4 and 6 mg/kg were used for the treatment of skin and soft tissue for infections and bacteraemia, respectively. However, increased doses of daptomycin are recommended for complicated infections by Gram-positive organisms. Methods: A systematic review was conducted using 4 databases. We compared treatment success between standard-dose (SD, 4–6 mg/kg) and high-dose (HD, >6 mg/kg) daptomycin in patients with all-cause bacteraemia, complicated bacteraemia, infective endocarditis, osteomyelitis and foreign body/prosthetic infection as the primary outcome. We also compared the success between SD and HD2 (≥8 mg/kg) daptomycin treatments in patients with these diseases as the secondary outcome. The incidence of creatine phosphokinase (CPK) elevation was evaluated as safety. Results: In patients with complicated bacteraemia and infective endocarditis, the treatment success was significantly lower in the SD group than in the HD group (odds ratio [OR] 0.48, 95% confidence interval [CI] 0.30–0.76 and OR 0.50, 95% CI 0.30–0.82) and HD2 group (OR 0.38, 95% CI 0.21–0.69 and OR 0.30, 95% CI 0.15–0.60), respectively. A significant difference was demonstrated only in the HD2 group in patients with bacteraemia, including simple infection. SD did not decrease the success rate for the treatment of osteomyelitis and foreign body/prosthetic infection. The incidence of elevated CPK was significantly lower in SD group than in HD group. Conclusion: SD daptomycin was associated with significantly lower treatment success than HD in patients with complicated bacteraemia/infective endocarditis. The CPK elevation should be considered in patients treated with high daptomycin doses.

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Optimal timing for therapeutic drug monitoring of voriconazole to prevent adverse effects in Japanese patients

Hanai Y., Ueda T., Hamada Y., Oda K., Takahashi Y., Nakajima K., Miyazaki Y., Kiriyama M., Uekusa S., Matsuo K., Matsumoto K., Kimura T., Takesue Y.

Mycoses （Mycoses） 66 （ 12 ） 1035 - 1044 2023年

共著, ISSN 09337407

Background: The optimal timing for therapeutic drug monitoring (TDM) of voriconazole in Asians, who have higher rates of poor metabolisers than non-Asians, is unclear. This can cause unexpectedly high concentrations and delays in reaching steady-state levels. Objectives: To determine the appropriate timing of TDM in Japanese patients receiving voriconazole. Patients/Methods: Trough levels (Cmin) were measured on days 3–5 (recommended timing, RT) and days 6–14 (delayed timing, DT) after starting voriconazole in patients receiving an appropriate dosage. Considering bioavailability, Cmin was only compared in patients receiving oral voriconazole. Results: A total of 289 and 186 patients were included in the safety and pharmacokinetic analyses, respectively. There was a significant difference in Cmin measured no later than and after day 5 (3.59 ± 2.12 [RT] vs. 4.77 ± 3.88 μg/mL [DT], p =.023), whereas no significant difference was observed on cutoff day 6 (3.91 ± 2.60 vs. 4.40 ± 3.94 μg/mL, p =.465), suggesting that Cmin close to the steady-state was achieved after day 5. DT causes a delay in achieving the therapeutic range. The hepatotoxicity rates were 21.5% and 36.8% in the RT and DT groups, respectively (p =.004); DT was an independent risk factor for hepatotoxicity. Conclusion: Although steady-state concentrations may not be achieved by day 5, early dose optimisation using RT can prevent hepatotoxicity in Japanese patients. TDM should be performed on days 3–5 to ensure safety. However, subsequent TDM may be necessary due to a possible further increase in Cmin.

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Analysis of Risk Factors for Developing Tuberculosis in Patients Who Received Prophylactic Latent Tuberculosis Infection Treatment with Experience of Biologic Medications

Itagaki M., Iketani O., Enoki Y., Chuang V.T.G., Taguchi K., Uno S., Uchida S., Namkoong H., Uwamino Y., Takano Y., Hasegawa N., Matsumoto K.

Biological & pharmaceutical bulletin （Biological & pharmaceutical bulletin） 46 （ 12 ） 1832 - 1837 2023年

共著, ISSN 0918-6158

Biologic medications have dramatically improved the treatment outcomes of immunological inflammatory diseases, but their immunosuppressive effects put patients at risk for tuberculosis (TB). We investigated the risk factors for developing TB in patients treated for latent tuberculosis infection (LTBI) who also had experience of using biologic medications. At Keio University Hospital, we retrospectively investigated patients treated with anti-mycobacterial drugs before or concurrently with biologic medications from January 2012 to August 2020. Patients in the 'follow-on cases group' who had a positive TB screening test after initiating biologic medications and subsequently started LTBI treatment were excluded. We researched and compared the patient characteristics for TB and non-TB patient groups. Of the 146 eligible patients, 5 (3.4%) developed TB. The incidence rate was 600/100000 person-years. There were no significant differences between TB and non-TB patient groups in the history of TB, interferon-gamma release assay (IGRA), duration of biologic medication therapy, LTBI treatment periods, concomitant use of calcineurin inhibitors or anti-rheumatic drugs. The percentage of patients who received prednisolone at a dose of ≥15 mg for more than 1 month was higher in those who developed TB than in those who did not (40.0 vs. 7.1%, p = 0.054); however, this difference was not statistically significant. Regular monitoring of TB is necessary for long-term concomitant use of high prednisolone doses during and after the administration of biologic medications.

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