Published papers

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.

Background: Understanding the vicious cycle driving renal impairment progression and skeletal muscle atrophy in chronic kidney disease (CKD) is crucial. Therefore, this study aimed to examine the role of transforming growth factor-beta (TGF-β) in promoting skeletal muscle atrophy in CKD. Methods: A combined model of 2/3 nephrectomy and unilateral ureteral ligation, as we previously reported, was used for CKD mice. Skeletal muscle weight and changes in skeletal muscle fiber twitch type were evaluated. Using C2C12 cells, a skeletal muscle myoblast cell line, molecules that induce a reduction in type IIa muscle fibers in CKD were identified. The identified molecule, TGF-β, was administered to mice to investigate its effects on muscle fiber-type changes. Furthermore, the effects of administering a TGF-β inhibitor to CKD mice were evaluated. Results: In CKD mice, myosin heavy chain (MyHC)-specific antibody immunostaining showed an increase in atrophied MyHC IIa (oxidative twitch) muscle fibers. CKD mouse serum preferentially induces MyHC IIa fiber atrophy in C2C12 cells. TGF-β-treated mice had reduced levels of oxidative metabolic skeletal muscle and oxidative type IIa fiber, similar to CKD mice. Furthermore, TGF-β inhibitor treatment prevented the CKD-associated decrease in oxidative type IIa muscle fiber size and reduced exercise capacity. Conclusions: These findings indicate that TGF-β causes skeletal muscle deterioration in CKD by reducing oxidative metabolism and inducing type IIa fiber atrophy. In addition, our results emphasize that reversing the disrupted MyHC phenotype in CKD is a potential therapeutic target for CKD-induced muscle atrophy.

Introduction: Nacubactam is a novel β-lactamase inhibitor with intrinsic antibacterial activity that shows therapeutic potential against carbapenemase-producing Enterobacterales when administered with β-lactam antibiotics. Pharmacokinetics/pharmacodynamics (PK/PD) analyses based on drug concentrations at the site of infection are recommended to better evaluate antibiotic efficacy. A new PD index, the instantaneous minimum inhibitory concentration (MICi), which dynamically reflects the changing susceptibility of β-lactams during co-administration with β-lactamase inhibitors, has recently been proposed. This study aimed to assess the efficacy of cefepime combined with nacubactam in a murine model of pneumonia using MICi-based PK/PD analysis in the lung epithelial lining fluid (ELF). Methods: In vitro pharmacodynamic testing using the checkerboard method was conducted with two β-lactamase-producing Klebsiella pneumoniae strains. In vivo PK and PD studies were performed in neutropenic mice using both β-lactamase-producing and non-producing strains. Drug concentrations in plasma and ELF were measured, and MICi-based PK/PD analysis was conducted. Results: In vitro, the MIC of cefepime decreased in a concentration-dependent manner with increasing nacubactam. In the murine model of pneumonia, cefepime monotherapy resulted in bacterial changes of 0.12–4.30 log10 CFU/lung, while the combination therapy reduced bacterial counts by −5.93 to −0.234 log10 CFU/lung. The percentage of time that free cefepime concentrations exceeded MICi (T > MICi) was highly correlated with bacterial reduction. The target T > MICi for maximal effect was estimated to be 29.3 %. Conclusions: These findings support the utility of MICi-based PK/PD analysis for optimizing combination antibiotic therapy in pneumonia.

Background: The Japanese Society of Chemotherapy developed practical area under the concentration-time curve (AUC)-guided therapeutic drug monitoring (PAT), a freely available web-based application widely used in Japan to support AUC-guided dosing of vancomycin. Its broad adoption has generated a substantial real-world pharmacokinetic database. Although PAT includes a preliminary pediatric model based on data from American children aged 3 months or older, that model requires further optimization. This study aimed to develop a population pharmacokinetic (popPK) model specifically for Japanese pediatric patients and to compare its performance with existing models. Methods: We utilized a real-world database collected through PAT between December 2022 and October 2024, comprising 1673 pediatric patients aged 3 months or older. Population pharmacokinetic analysis was performed using nonlinear mixed-effects modeling, with comparisons made against 5 existing models. Results: The developed model demonstrated strong a priori predictive performance for empirical vancomycin dosing, with a mean prediction error of 0.2 μg/mL and a mean absolute prediction error of 5.6 μg/mL. These results showed no apparent bias. Graphical diagnostics confirmed optimal a priori prediction in the developed model. A posteriori predictive performance—used for Bayesian posterior dosing—was similarly favorable across all models. Notably, 2-point sampling produced significantly different clearance estimates compared with 1-point sampling in 21 of 116 patients (18.1%). Conclusions: For Japanese pediatric patients aged 3 months or older, the developed popPK model is suitable for both empirical and Bayesian-guided vancomycin dosing. Two-point sampling improves the accuracy of clearance estimation and is recommended when feasible.

Introduction In patients with diminished muscle mass, serum creatinine (SCr) levels may be misleadingly low, potentially leading to overestimations of kidney function and unexpectedly high blood levels of vancomycin. This study aimed to identify factors contributing to this discrepancy and develop a flowchart for stratifying the risk of excessive vancomycin exposure, measured as an upward deviation in the area under the concentration-time curve (AUC) in patients with low SCr levels. Methods We analyzed data from patients who received vancomycin and had an SCr value <0.6 mg/dL. The discrepancy between the AUC24-48 h initial dosing and AUC24-48 h TDM was calculated; a ratio (AUC24-48 h TDM/AUC24-48 h initial dosing) higher than 1.2 defined an upward deviation in the AUC. A decision tree model was constructed using classification and regression tree algorithms. Results Among the 95 patients (median age [interquartile range], 69 [58, 80] years; 68% female), the upward AUC deviation was 40% (38/95). Three factors (creatinine clearance: 115 ml/min, age: 69 years, and blood urea nitrogen/SCr: 17) were selected for the decision flowchart and included in four subgroups. Conclusion We developed a flowchart to identify patients with low SCr levels whose AUC at therapeutic drug monitoring deviated upward by >20% from the predicted AUC.

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

Purpose: This study evaluated the population pharmacokinetics of daptomycin in nonobese elderly patients with hypoalbuminemia and chronic kidney disease (CKD) using the glomerular filtration rate estimated from cystatin C (eGFRcys) and estimated its optimal dose. Methods: We performed population pharmacokinetic analysis of the unbound concentrations of daptomycin. The probability of target attainment of 90% for achieving an area under the concentration–time curve of unbound daptomycin at steady state/ minimum inhibitory concentration ratio of ≥66.6 was stochastically simulated. Results: In the population pharmacokinetic analysis of 25 patients aged ≥65 years, the two-compartment model using eGFRcys and age as covariates of clearance in central compartment of unbound daptomycin were optimal. The unbound fraction rate (fu) was 0.05–0.14. According to the Monte Carlo simulation, the optimal doses for patients with eGFRcys of 20–60 mL/min and aged 65–95 years were calculated as 200–500 mg q24h. Conclusion: These results suggest that establishing the dose using total concentrations may result in under- or overestimation caused by alterations in fu. The optimal dose for nonobese elderly patients with hypoalbuminemia and CKD depends on eGFRcys and age, and a standard dose may be insufficient for some patients.

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.

Objectives This study clarified the target values of VAN against Enterococcus faecium using pharmacokinetics/pharmacodynamics (PK/PD) analysis and compared a downsized hollow fibre infection model (HFIM) with a conventional HFIM. Methods VAN was administered subcutaneously and blood concentrations were measured to calculate the PK parameters. PD studies were performed in an infected mouse model by administering VAN at doses ranging from 25 to 400 mg/kg based on PK parameters. PK/PD parameters correlated with antimicrobial efficacy were determined, and a target value of 2 log10 kills was calculated. The efficacy of VAN against E. faecium was evaluated by reproducing the VAN PK in the plasma at doses that achieved the target value using conventional and novel downsized HFIMs. Results PK/PD analysis showed that fAUC/minimum inhibitory concentration (MIC) demonstrated the most relevant index, with a target value of 249 to achieve a 2 log10 kill. Blood concentrations of 750 mg VAN every 12 h (equivalent to 260 fAUC/MIC) were simulated well with both HFIMs. Changes in E. faecium caused by continuous exposure to VAN resulted in a reduction in bacterial counts by ∼6.0 log10 kill 168 h after the start of treatment in both models. Downsizing reduced the extracapillary space volume, circulating medium, amount of drugs used and infectious waste. The total cost of the downsized cartridge system was approximately half that of the conventional model system. Conclusions We established a downsized HFIM and demonstrated its viability as a cost-effective and environmentally sustainable in vitro PK/PD. The findings highlighted its potential as a future PK/PD analysis standard.

Background: Although vancomycin is commonly used to treat Enterococcus faecium infections, there are no clear guidelines for the optimal 24-h area under the concentration time curve to minimum inhibitory concentration (AUC24/MIC) ratio. This study aimed to determine the target AUC24/MIC ratio associated with vancomycin-treated E. faecium infection outcomes. Methods: This retrospective multicenter cohort study included adult patients who received vancomycin for ≥5 days for E. faecium-associated bloodstream infections between January 2018 and December 2023. The primary outcome was treatment success, defined as a composite of survival beyond 30 days, clinical success, and microbiological eradication. Secondary outcomes included 30-day mortality, clinical success, microbiological eradication, and nephrotoxicity. Receiver operating characteristic (ROC) curve analysis identified the AUC24/MIC cut-off value for treatment success. Multivariate regression analysis was used to determine the association between AUC24/MIC and outcomes. Results: This study included 81 patients. ROC analysis identified AUC24/MIC ≥427 as the cutoff value for treatment success. The overall treatment success rate (71.6 %) was significantly higher in the above AUC24/MIC cut-off group (81.8 %) than in the below AUC24/MIC cut-off group (59.5 %). On multivariate analysis, AUC24/MIC ≥427 was an independent predictor (adjusted odds ratio: 4.399, 95 % confidence interval: 1.203–19.320, p = 0.024) of treatment success. The clinical success and microbiological eradication rates differed significantly between the below- and above-cut-off groups, whereas nephrotoxicity rates were comparable between the groups. Conclusions: In treating E. faecium infections, vancomycin AUC24/MIC ratio ≥427 was independently associated with treatment success. However, further prospective studies are required to confirm the AUC24/MIC target.

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.

Area under the concentration–time curve (AUC)-guided vancomycin treatment is asso-ciated with decreased nephrotoxicity. It is preferable to obtain two samples to estimate the AUC. This study examined the usefulness of AUC estimation via trough concentration (Cmin )-only sampling of 260 adults infected with methicillin-resistant Staphylococcus aureus (MRSA) who received vancomycin. The exact Cmin sampling time was used for Bayesian estimation. A significantly higher early treatment response was observed in patients with a day 2 AUC ≥ 400 µg·h/mL than those with <400 µg·h/mL, and a significantly higher early nephrotoxicity rate was observed in patients with a day 2 AUC ≥ 600 µg·h/mL than those with <600 µg·h/mL. These AUC cutoff values constituted independent factors for each outcome. In sub-analysis, the discrimination ability for early clinical outcomes using these AUC cutoffs was confirmed only in patients with q12 vancomycin administra-tion. A significant difference in early treatment response using the 400 µg·h/mL cutoff was obtained only in patients with low-risk infections. The usefulness of the vancomycin AUC target to decrease nephrotoxicity while assuring clinical efficacy was even confirmed with a single Cmin measurement. However, assessment with two samples might be required in patients with q24 administration or high/moderate-risk MRSA infections.

The chemical modification of proteins is an effective technique for manipulating the properties and functions of proteins, and for creating protein-based materials. The N-terminus is a promising target for single-site modification that provides modified proteins with uniform structures and properties. In this paper, a copper(II)-mediated aldol reaction with 2-pyridinecarboxaldehyde (2-PC) derivatives is proposed as an operationally simple method to selectively modify the N-terminus of peptides and proteins at room temperature and physiological pH. The copper(II) ion activates the N-terminal amino acids by complexation with an imine of the N-terminal amino acid and 2-PCs, realizing the selective formation of the nucleophilic intermediate at the N-terminus. This results in a stable carbon-carbon bond between the 2-PCs and the α-carbon of various N-terminal amino acids. The reaction is applied to four different proteins, including biopharmaceuticals such as filgrastim and trastuzumab. The modified trastuzumab retains the human epidermal growth factor receptor 2 recognition activity.

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.

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.

Background: The impact of shortening or extending a vancomycin dosing interval on early attainment of target blood levels and acute kidney injury (AKI) remains unclear. We investigated the relationship between the interval of the first and second doses of vancomycin and early area under the concentration-time curve (AUC) and AKI. Methods: Patients (≥ 18 years) who started vancomycin and had trough/peak blood samples were included. The definition of shortened interval as the first and second doses of vancomycin was < 12 h. The cumulative incidence of AKI within 21 days was compared using the shortened interval and AUC on day 1 and 2. Results: Among 668 patients (median age 69 [interquartile range (IQR): 57, 78] years, 40% female), the proportion achieving an AUC ≥ 400 µg·h/mL on day 1 was significantly higher in the shortened-interval group (82% vs. 50%; p < 0.001). Multivariate analysis revealed no association between a shortened interval (hazards ratio [HR], 1.10 [95% confidence interval (CI), 0.63–1.91]; p = 0.750) or an AUC > 600 µg·h/mL on day 1 alone (HR, 2.17 [95% CI, 0.64–7.42]; p = 0.220) and AKI onset. However, an AUC > 600 µg·h/mL on day 2 alone (HR, 2.92 [95% CI, 1.45–5.87]; p = 0.003) or on both days (HR, 11.18 [95% CI, 5.07–24.67]; p < 0.001) was significantly associated with increased AKI risk. Conclusions: Shortening the dosing interval facilitates early achievement of target AUC without increasing AKI risk, provided AUC on day 2 is appropriately controlled.

© 2020 The Authors Objectives: Pharmacokinetic/pharmacodynamic (PK/PD) analysis using murine infection models is a well-established methodology for optimising antimicrobial therapy. Therefore, we investigated the PK/PD indices of teicoplanin againstStaphylococcus aureus using a murine thigh infection model. Methods: Mice were rendered neutropenic by administration of a two-step dosing of cyclophosphamide. Then, isolates of methicillin-susceptibleS. aureus (MSSA) or methicillin-resistant S. aureus (MRSA) were inoculated into the thighs of neutropenic mice. PK/PD analyses were performed by non-linear least-squared regression using the MULTI program. Results: Target values offCmax/MIC (r2 = 0.94) of teicoplanin for static effect and 1 log10 kill against MSSA were 4.44 and 15.44, respectively. Target values of fAUC24/MIC (r2 = 0.92) of teicoplanin for static effect and 1 log10 kill against MSSA were 30.4 and 70.56, respectively. Target values of fCmax/MIC (r2 = 0.91) of teicoplanin for static effect and 1 log10 kill against MRSA were 8.92 and 14.16, respectively. Target values of fAUC24/MIC (r2 = 0.92) of teicoplanin for static effect and 1 log10 kill against MRSA were 54.8 and 76.4, respectively. Conclusion: These results suggest thatfCmax/MIC and fAUC24/MIC are useful PK/PD indices of teicoplanin against MSSA and MRSA.

© 2020 The Japanese Society for the Study of Xenobiotics Dolutegravir (DTG) is an integrase inhibitor, whose gastrointestinal absorption is impaired by the formation of chelates with multivalent metal cation preparations. However, little is known regarding the interactions of DTG with preparations containing other multivalent metal cations or with polycation polymer preparations. This study examined how the pharmacokinetics of DTG are affected by co-administration with Al(OH)3, LaCO3, and the polycation polymers bixalomer (Bxl) and sevelamer (Svl). Prior to oral administration of DTG (5 mg/kg), rats were orally administered Al(OH)3 (150 or 300 mg/kg), LaCO3 (50 or 75 mg/kg), Bxl (250 or 500 mg/kg), or Svl (300 or 600 mg/kg). Serum concentrations of DTG were then measured over the next 24 h. Compared to the administration of DTG alone, its co-administration with Al(OH)3, LaCO3, Bxl, and Svl led to reduced serum concentration of DTG, and consequently, a significantly reduced area under the curve. These comparisons also revealed a considerable reduction in the maximum concentration, suggesting that the interactions of these agents with DTG in the intestinal tract inhibit absorption of DTG. The above results demonstrate that Al(OH)3, LaCO3, Bxl, and Svl affect the pharmacokinetics of DTG and indicate the need for caution when combining any of the above preparations with DTG.

Colistin methanesulfonate (CMS) is a cyclic polypeptide antibiotic with neurotoxic side effects. Sevoflurane (Sevo), an inhaled anesthetic, is known to enhance the non-depolarizing effect of neuromuscular relaxants; however, its mechanism of action is unclear. In this study, we investigated the augmentation effect of Sevo on CMS-induced neurotoxicity. We prepared a sciatic nerve-skeletal muscle stimulation model using Sprague-Dawley male rats administered CMS with or without Sevo. The muscle contraction inhibition rate was determined from electromyogram measurements. Furthermore, we simulated the pharmacokinetics of CMS and colistin using previous reports, and the relationship between the effect of muscle contraction inhibition and pharmacokinetic parameters was evaluated. We observed a dose-dependent neuromuscular inhibitory effect of Sevo under CMS administration. The 50 % inhibitory dose (ID50) values for CMS and CMS+Sevo were 167 ± 12 and 85 ± 5 mg/kg, respectively. The combination of CMS with Sevo showed a 49 % decrease in the ID50 compared with CMS alone. The simulated area under the time–concentration curve (AUC) values for CMS and colistin administration in rats at 200 mg/kg were 219 and 16.0 mg·h/L, respectively. The predicted AUC values of colistin corresponding to the ID50 at 0–45 min for CMS alone and CMS+Sevo were 12.0 and 7.0 mg·h/L, respectively. We revealed that the neurotoxic effect of CMS was enhanced by the concomitant use of Sevo. Based on the simulated AUC values, we concluded that this neurotoxic effect may also occur in clinical settings, and concomitant use of CMS and Sevo should be avoided.

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.