Published papers

We evaluated heparinoid-containing soft ointments and heparinoid-containing creams to develop information useful to select drugs. Spreadability, consistency and the water content of stratum corneum was measured. A selection table focusing on impression of the use was prepared. Spreadability of the semi-original soft ointment and cream were lower than those of all generic drugs. Regarding hardness, one generic soft ointment was softer than the semi-original drug, but the semi-original cream was harder than all generic creams. Regarding the impression of the use, a significant difference was noted in smell in soft ointments, and 6 items in creams. Correlation was found between the spreadability and consistency test results and impression of the use. A significant difference was noted in the water content of stratum corneum in creams. The selection table prepared based on the impression of the use may provide information that helps selection of preparations in clinical practice.

Clostridioides difficile (C. difficile) colitis and pseudomembranous colitis are known as healthcare-associated intestinal infections. In this study, the incidence of C. difficile colitis and pseudomembranous colitis was investigated using the Japanese Adverse Drug Event Report (JADER). Using JADER data between April 2004 and September 2017, the patient who developed C. difficile colitis and pseudomembranous colitis were investigated. During the study period, 375 cases of C. difficile colitis and 903 cases of pseudomembranous colitis were reported. The numbers of reported cases of both C. difficile colitis and pseudomembranous colitis were largest in those in their 70s, accounting for 24.7% and 25.6%, respectively. Patients in their 60s-90s comprised the majority of all patients with both C. difficile colitis and pseudomembranous colitis. Both C. difficile colitis and pseudomembranous colitis were caused by antibiotics in many patients, and signals of all antibiotics were detected. In C. difficile colitis, signals of immunosuppressants, corticosteroids, and alkylating drugs were also detected among drugs other than antibiotics. For pseudomembranous colitis, the use of molecularly targeted drugs, antimetabolic drugs, and corticosteroids was reported other than antibiotics. Using JADER, we revealed risk factors for the development of C. difficile colitis and pseudomembranous colitis, and firstly revealed that molecularly targeted drugs other than antibiotics could also be potential risk factors. Our findings may be useful for the early detection of drug-induced C. difficile colitis and pseudomembranous colitis.

The major adverse event associated with linezolid treatment is reversible myelosuppression, mostly thrombocytopenia. Recent studies have reported that the incidence of linezolid-induced thrombocytopenia was higher in patients with renal failure than in patients with normal renal function, although the underlying mechanisms of this toxicity are still unknown. The present study thus aimed to investigate the relationship between renal function and linezolid exposure as well as the effects of drug exposure on thrombocytopenia. A statistically significant (P < 0.01) strong correlation (r = 0.933) was observed between linezolid clearance and creatinine clearance. A negative correlation (r = -0.567) was also shown between linezolid clearance and blood urea nitrogen, although the correlation was not statistically significant. In thrombocytopenic patients, the trough concentration was 14.4-35.6 mg/L and the area under the plasma linezolid concentration-time curve for 24 h (AUC(24 h)) was 513.1-994.6 mg h/L; in non-thrombocytopenic patients, drug exposure was relatively low (6.9 mg/L and 7.2 mg/L for trough concentration and 294.3 mg h/L and 323.6 mg h/L for AUC(24 h)). These results provide a pharmacokinetic explanation for the mechanism of the adverse event that renal dysfunction increased linezolid trough concentration and AUC and that higher drug exposure induced thrombocytopenia. (C) 2010 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.

Linezolid pharmacokinetic profile in pediatric patients has not been fully characterized, and the dose needed to achieve a pharmacokinetic-pharmacodynamic (PK-PD) target has yet to be established because its efficacy is associated with the area under the plasma drug concentration time curve (AUC(24))/minimum inhibitory concentration (MIC) ratio. The present study aimed to define the pharmacokinetic parameters of intravenous linezolid in pediatric patients and assess the rationale for the approved dosage recommendations. Linezolid was safe, tolerated well, and clinically effective for treating Gram-positive bacteria in five pediatric patients (3-11 years). The mean values for the volume of distribution, and total clearance (CL) in a one-compartment model were estimated to be 0.646 +/- 0.239 l/kg and 0.171 +/- 0.068 1/h/kg, respectively (mean +/- S.D.). Based on this analysis, the AUC(24) and trough drug concentration in plasma (C-min) for linezolid doses were predicted to be 175.4 mu g h/ml and 3.4 mu g/ml for 30 mg/kg/day, 204.7 mu g h/ml and 4.3 mu g/ml for 35 mg/kg/day, and 2632 mu g h/ml and 6.2 mu g/ml for 45 mg/kg/day, respectively. Taking into account that AUC(24) should be >= 200 mu g h/ml for MIC of 2.0 mu g/ml (to achieve an AUC(24)/MIC ratio of >= 100) and C-min should be approximately 7 mu g/ml (to avoid thrombocytopenia), we consider the approved dosage of 30 mg/kg/day to be fundamentally rational, but can be underdosed against bacteria with MIC of 2.0 mu g/ml; therefore, a dose of 35-45 mg/kg/day is more appropriate to ensure the efficacy and safety of linezolid in pediatric patients. (C) 2014, Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

The antimicrobial agents vancomycin and metronidazole have been used to treat Clostridium difficile infections (CDIs). However, it remains unclear why patients are at risk of treatment failure and recurrence. Therefore, this study retrospectively examined 98 patients with CDIs who were diagnosed based on the detection of toxin-positive C. difficile to determine the risk factors affecting drug treatment responses and the recurrence of CDI. No significant difference was observed in the cure rate or dosage between the vancomycin and metronidazole groups. The 90-d mortality rate and total number of drugs associated with CDIs, including antiinfective agents used within 2 months before the detection of toxin-positive C. difficile, were significantly lower in the treatment success group than in the failure group. The total number of antiinfective agents and gastric acid-suppressive agents used during CDI therapy was also significantly lower in the success group than in the failure group. The period from the completion of CDI therapy to restarting the administration of anticancer agents and steroids was significantly longer in patients without than in patients with recurrence. These results indicate that the total number of drugs associated with CDIs should be minimized to reduce the risk of CDIs, that not only antibiotics but also gastric acid-suppressive agents should be discontinued during CDI therapy to increase therapeutic efficacy, and that the use of anticancer agents and steroids should be delayed as long as possible after patients are cured by CDI therapy to prevent recurrence.

Hepatitis B caused by chemotherapy- and immunosuppression-associated hepatitis B virus reactivation is likely to become fulminant, and a high mortality rate has been reported. In this study, using the Japanese adverse drug event report database (JADER), factorial analysis of patients who developed hepatitis B as an adverse event was performed. The number of reported cases of hepatitis B during the survey period was 781 and 185 of them (24%) died. Rituximab and prednisolone were administered to many cases (233, 216 cases, respectively), and the reporting odds ratios were high (65.35, 13.40, respectively), suggesting their strong association with the development of hepatitis B. Regarding the onset time, rituximab-induced hepatitis B developed within one year after administration in 83%, being a high frequency. Prednisolone-induced hepatitis B developed even after one year in 36%. Since prednisolone is used to treat rheumatoid arthritis at a dose <= 10mg/d, the patients were divided based on the prednisolone dose into the groups treated at >10 and <= 10 mg/d, and the onset time was investigated in each group. The median onset time was 113 and 330d, respectively, showing a significant difference. On time-to-event analysis using the Weibull distribution, rituximab was classified as the early failure type, and prednisolone and methotrexate for rheumatoid arthritis were classified as the wear out failure type. These findings are important information which may lead to early discovery of and taking actions against hepatitis B being helpful for providing appropriate medical care.

An initial loading procedure has been recommended to enable teicoplanin to promptly reach an effective serum concentration for the treatment of methicillin-resistant Staphylococcus aureus (MRSA). This study aimed to retrospectively evaluate the pharmacokinetics and pharmacodynamics of teicoplanin to determine the therapeutic target for the teicoplanin trough concentration and an appropriate dosing method during the first 3 days. The mean trough concentrations were 13.2 mg/L for patients with eradication of MRSA. Moreover, logistic regression analysis showed that the teicoplanin trough concentration was 13 mg/L to achieve MRSA eradication with a probability of 89.0%. The rates of achieving a parts per thousand yen13 mg/L in a parts per thousand currency sign24, 24-36 and a parts per thousand yen36 mg/kg (total dose during the first 3 days) groups were 9.1, 48.4 and 87.5%, respectively. These results suggest that the administration of a parts per thousand yen36 mg/kg during the first 3 days is appropriate to promptly obtain a trough concentration target of a parts per thousand yen13 mg/L for the initial treatment of MRSA infections.

Arbekacin (ABK) was approved and widely used in Japan for treatment of patients infected with MRSA, and TDM was introduced in clinical practice. The Japanese Society of Chemotherapy and the Japanese Society of Therapeutic Drug Monitoring decided to develop a clinical practice guidelines for TDM of ABK for the following reasons. First, although the daily dose of 150-200 mg was approved in Japan, recent PR-PD studies revealed that higher serum concentration is required to achieve better clinical efficacy and several findings concerning the usefulness of higher dosage regimen have obtained recently. Second, although maximal concentrations that obtained immediately after the end of administration (C-max) was generally adopted, the serum concentration at 1 h after initiation of administration [peak serum concentration (C-peak)] proved to be more suitable as an efficacy indicator of aminoglycosides. Lastly, as ABK is approved only in Japan, no international practice guideline for TDM has not been available in ABK to date. This guideline evaluated the scientific data associated with serum ABK monitoring and provided recommendations based on the available evidence. Potential limitations of this guideline, however, include the findings that few prospective clinical trials of TDM of ABK are available in the treatment of MRSA infections and that most of the published literature describes observational studies. (C) 2013, Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

Human a1-acid glycoprotein (AGP), a serum glycoprotein, is known to have anti-inflammatory activity. We recently reported that AGP was mainly incorporated into the liver in mice via a receptor-mediated pathway, although the mechanism for this was largely unknown. The objective of this study was to identify the specific cellular surface protein that recognizes the peptide moiety of AGP. Pharmacokinetic studies of 111InAGP and 111In recombinant glycan-deficient AGP (rAGP) in mice demonstrated that both AGPs are mainly distributed to the liver and kidney, but hepatic and renal uptake clearance of rAGP was higher than that for AGP. Hepatic uptake of rAGP was inhibited in the presence of 100-fold excess of unlabeled AGP, indicating that the hepatic uptake of rAGP shared a common route with that of AGP and that it recognized the peptide moiety of AGPs. In ligand blotting analyses using crude cellular membrane fraction of mice liver, a band corresponding to a 16 kDa protein was observed to bind to both AGPs. Interestingly, matrix-assisted laser desorption ionizationtime-of-flight mass spectrometry MALDITOF-MS and western blotting analyses indicated that this 16 kDa protein is the hemoglobin beta-chain (HBB). It, therefore, appears that HBB is associated with the hepatic uptake of AGP via a direct interaction with its peptide moiety. (c) 2011 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 101:15991606, 2012

Optimal use of carbapenems is an important issue in the prevention of resistance in Pseudomonas aeruginosa. In this study, we investigated the correlation between antimicrobial use density (AUD) of carbapenems and imipenem/cilastatin (IPM/CS) or meropenem (MEPM) susceptibility of P. aeruginosa strains. The AUD of five carbapenems [IPM/CS, panipenem/betamipron, biapenem, MEPM and doripenem (DRPM)] was examined every 6 months between 2006 and 2008. The AUD was calculated using the defined daily doses methodology developed by the World Health Organisation. A minimum inhibitory concentration of IPM/CS or MEPM of <= 4 mg/L was considered to be sensitive. There was a significant negative correlation between MEPM susceptibility and the total AUD of MEPM and DRPM [r = -0.823, 95% confidence interval (CI) -0.035 to -0.980; P = 0.044]. Furthermore, there was a significant correlation between MEPM susceptibility and IPM/CS susceptibility (r = 0.839, 95% CI 0.084 to 0.981; P = 0.037). Cross-resistance was therefore investigated and only 5.6% of MEPM-insensitive strains were susceptible to IPM/CS, although 43.3% of IPM/CS-insensitive strains were susceptible to MEPM. These results suggest that curtailing the use of MEPM and DRPM may curb the emergence not only of MEPM-resistant strains but also IPM/CS-resistant strains. (C) 2009 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.

Voriconazole metabolism is mostly mediated via the cytochrome P450 (CYP) 2C19 isozyme. The non-wild (mutant) type of CYP2C19 is generally found in 60-70% of Asian populations. Because the voriconazole trough plasma concentration has been reported to correlate with hepatotoxicity, this study investigated the effect of CYP2C19 polymorphism on the relationship between voriconazole trough concentrations and liver function abnormalities in 29 Japanese patients with fungal infections (CYP2C19 wild-type, n = 10; non-wild-type, n = 19). Hepatotoxicity, defined as liver enzyme abnormality according to the National Cancer Institute criteria, was observed in 10 (34.5%) of 29 patients with a trough concentration >= 3.9 mg/L. Logistic regression analysis suggested that the therapeutic range for the voriconazole trough concentration should be 2-4 mg/L. Non-linear pharmacokinetic analysis suggested that voriconazole therapy should be initiated with a dose of 7.2-8.9 mg/kg/day for CYP2C19 wild-type and 4.4-6.5 mg/kg/day for the non-wild-type in Japanese patients. These recommended initial dosages and subsequent dose adjustment for the target concentration range by therapeutic drug monitoring should avoid adverse events and thus enable continued effective voriconazole therapy for Japanese patients with mycoses. (C) 2009 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.

The pharmacokinetic/pharmacodynamic (PK/PD) index for the efficacy of linezolid is a 24-h area under the plasma drug concentration-time curve (AUC(24))/minimum inhibitory concentration (MIC) ratio of >= 100. The main adverse event associated with administration of linezolid is thrombocytopenia. Therefore, the aims of the present study were to define PD thresholds that would minimise linezolid-induced thrombocytopenia and to perform a population PK analysis to identify factors influencing the pharmacokinetics of linezolid. Population PK analysis revealed that creatinine clearance (CLCr) significantly affected linezolid pharmacokinetics: the mean parameter estimate of drug clearance (CL; in L/h)= 0.0258 x CLCr + 2.03. A strong correlation (r=0.970) was found between AUC(24) and trough plasma concentrations (C.) [AUC(24)=18.2 x C-min + 134.4]. The Cmin value for AUC(24)=200 (in the case of MIC=2 mu g/mL) was estimated to be 3.6 mu g/mL. Regarding safety, Cmin was a significant predictor of thrombocytopenia during treatment, and its threshold to minimise linezolid-induced thrombocytopenia was 8.2 mu g/mL. A Kaplan-Meier plot revealed that the median time from initiation of therapy to the development of thrombocytopenia was 15 days. Therefore, the target C. range was 3.6-8.2 mu g/mL. The following formula to achieve a target C. in patients with different degrees of renal function was proposed based on these results: initial daily dose (mg/day) = CL x AUC(24) = (0.0258 x CLCr + 2.03) x (18.2 x C-min + 134.4). This recommended initial dosage and subsequent dosage adjustment for the target concentration range should avoid adverse events, thereby enabling effective linezolid-based therapies to be continued. (C) 2014 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.

The immunomodulatory activity of linezolid has recently been reported using in vitro experimental models. However, the anti-inflammatory activity of linezolid has not yet been demonstrated using in vivo experimental models. Therefore, the aim of the present study was to demonstrate the anti-inflammatory activity of linezolid and other anti-MRSA agents using the carrageenan-induced rat paw edema model.The pretreatment with 50 mg/kg linezolid significantly suppressed edema rates, compared with control (5% glucose), with edema rates at 0.5 and 3 h after the administration of carrageenan being 17.3 ± 3.5 and 30.8 ± 3.0%, respectively. On the other hand, edema rates were not suppressed by the pretreatments with 50 mg/kg vancomycin, teicoplanin, arbekacin, and daptomycin. Furthermore, we demonstrated that linezolid exhibited anti-inflammatory activity in a concentration-dependent manner. These effects were observed at linezolid concentrations that are achievable in human serum with conventional dosing.In conclusion, the results of the present study suggest that the anti-inflammatory activities of linezolid, in addition to its antimicrobial effects, have a protective effect against destructive inflammatory responses in areas of inflammation.

Teicoplanin is a glycopeptide antibacterial agent that has a long serum half-life and therefore takes time to achieve steady-state conditions. An appropriate initial dosing is needed for teicoplanin to promptly reach an effective serum trough concentration. However, little information is available on tailoring the initial dosing for patients with various characteristics. The objective of this study was to develop a nomogram for determining teicoplanin initial dose to promptly reach an effective trough concentration (a parts per thousand yen13 mu g/mL). A logistic regression analysis was performed to test whether the area under the concentration time curve (AUC) is a significant predictor of microbiological response (persistence 0; eradication 1). The study included 24 adult patients with methicillin-resistant Staphylococcus aureus infections [minimal inhibitory concentration (MIC) for the isolates was < 2 mu g/mL). Each AUC was estimated using individual dose, creatinine clearance (CL(cr)), and body weight data. The target value, which gives about a 0.9 microbiological eradication probability, was 750 mu g h/mL for AUC from zero to 24 h (AUC(0-24 h)). Using published population pharmacokinetic parameters, the dose required to achieve the AUC(0-24 h) target was calculated as dose (mg) = 750 x (0.00498 x CL(cr) (mL/min) + 0.00426 x body weight (kg). For various combinations of CL(cr) and body weight, we checked the calculated doses using a therapeutic drug monitoring (TDM)-supporting software and developed a nomogram. The nomogram would be useful for initial dose adjustment to promptly reach an effective serum trough concentration and avoid adverse events of teicoplanin.

Background: Methicillin-resistant Staphylococcus aureus (MRSA) is a frequent cause of orthopedic surgical site infections (SSIs). The aim of this study was to evaluate the effect of a bundle approach in the prevention of orthopedic MRSA SSIs. Material and Methods: MRSA active surveillance and decolonization were performed preoperatively at our institution from July 2004 until 2007. In January 2008, a bundle approach comprising contact precautions for MRSA-positive patients and cefazolin-based antimicrobial prophylaxis (AMP) stewardship was implemented. Data on the prevalence of MRSA SSIs, antimicrobial use density, duration of AMP, and the use of an alcohol antiseptic agent (L/1,000 patient-days) were evaluated during 2 periods: July 2004-December 2007 (period A) and January 2008-December 2012 (period B). Results and Discussion: The MRSA SSI rate during period B (0.97%; 19 out of 1,966) was significantly lower than that during period A (2.17%; 29 out of 1,333; P =.003). The infection rate correlated negatively with both the cefazolin antimicrobial use density (r = -0.76; P = .0002) and the use of an alcohol antiseptic agent (r = -0.68; P = .002). Conclusions: An infection-prevention bundle consisting of contact precautions for carriers and AMP stewardship in addition to active surveillance was associated with a significant decrease in the incidence of orthopedic MRSA SSIs. Copyright (c) 2016 by the Association for Professionals in Infection Control and Epidemiology, Inc. Published by Elsevier Inc. All rights reserved.