In our hospital, a full-time pharmacist specializing in antimicrobial therapy joined the newly la... more In our hospital, a full-time pharmacist specializing in antimicrobial therapy joined the newly launched antimicrobial stewardship team in May 2018, and started daily monitoring to optimize the use of broad-spectrum antimicrobials. For the medical staff to better understand antimicrobial therapy, the educational lectures were conducted four times after intervention. This study aimed to evaluate the impact of a full-time pharmacist's intervention on antimicrobial stewardship. The effects before (May-December 2017) and after the intervention period (May-December 2018) on antibiotic therapy and clinical outcomes were compared. The rate of blood culture collections before starting broad-spectrum antibiotics significantly increased after intervention (71% vs. 82%, p < 0.001), and initially prescribed broad-spectrum antibiotics were significantly de-escalated (55% vs. 78%, p = 0.004). A significant reduction in the monthly use of antipseudomonal antibiotics was observed (50.5 vs. 41.8 defined daily doses per 1000 patient-days, p = 0.01). The incidence of hospital-acquired Clostridioides difficile infection (HA-CDI) significantly decreased after intervention (1.12 vs. 0.54 cases per 10,000 patient-days, p = 0.033). The 30-day mortality rate did not change between the two periods (19.4% vs. 17.7%, p = 0.61). Our intervention ensured appropriate antimicrobial therapy and reduced the incidence of HA-CDI without worsening the clinical outcomes.
Our antimicrobial pharmacist-led intervention included: (a) a structured review of antibiotic pre... more Our antimicrobial pharmacist-led intervention included: (a) a structured review of antibiotic prescriptions; (b) educating prescribers on antimicrobial therapy; (c) monthly reporting of department-level rates of blood sampling for culture. Daily review began in May 2018 and was discontinued after 10 months; however, the other interventions were conducted throughout the study period. This study aimed to evaluate the sustained impact of pharmacist’s interventions on antimicrobial therapy and clinical outcomes between the baseline (May–December 2017), intervention (May–December 2018), and post-intervention (May–December 2019) periods. The rate of blood culture collections before starting antipseudomonal agent therapy was significantly increased from the baseline to post-intervention periods (71% vs. 85%, p < 0.001). Antipseudomonal agent therapy was more frequently de-escalated in the post-intervention period than in the baseline period (73% vs. 54%, p = 0.038). Total use of antipse...
AbstractPurpose. The purpose of this study was to clarify the mechanism of pharmacokinetic intera... more AbstractPurpose. The purpose of this study was to clarify the mechanism of pharmacokinetic interaction between cyclosporin A and probucol in clinical cases. Methods. The whole blood concentration of cyclosporin A was measured after oral administration of cyclosporin A with or without probucol in rats. Cyclosporin A was administered as three types of solutions: the contents of the conventional formulation (Sandimmun® capsule) diluted with corn oil and the contents of the new microemulsion preconcentrate formulation (Neoral® capsule) diluted with saline or corn oil. The solubility of cyclosporin A and another lipophilic agent tacrolimus in water with or without probucol was also measured. Results. The area under the blood concentration-time curve (AUC) after the administration of Sandimmun® (corn oil) and Neoral® (corn oil) was significantly decreased to 26% and 41% of the control by coadministration of probucol. However in the case of Neoral® (saline), it was unchanged. The terminal ...
Since 2014, several global and national guidelines have been introduced to address the problem of... more Since 2014, several global and national guidelines have been introduced to address the problem of antimicrobial resistance. We conducted a campaign in a tertiary hospital to promote appropriate quinolone use through educational lectures in 2018. The aim of this retrospective study was to evaluate the changes in the following: prescription characteristics, trend of oral quinolone use, and antibiotic susceptibility of bacteria from 2013 to 2020. Antimicrobial use was assessed as days of therapy per 1000 patient-days. We found a significant reduction in unnecessary antibiotic prescriptions between December 2013 and December 2020. Significant negative trends were detected in the use of quinolones over 8 years (outpatients, coefficient = −0.15655, p < 0.001; inpatients, coefficient = −0.004825, p = 0.0016). In particular, the monthly mean use of quinolones among outpatients significantly decreased by 11% from 2013 to 2014 (p < 0.05) and reduced further by 31% from 2017 to 2020 (p &...
The incidence of bacteremia caused by Enterococcus faecium, which is highly resistant to multiple... more The incidence of bacteremia caused by Enterococcus faecium, which is highly resistant to multiple antibiotics, is increasing in Japan. However, risk factors for the acquisition of E. faecium infection and mortality due to enterococcal bacteremia are not well known. We compared demographic, microbiological, and clinical characteristics using a Cox regression model and univariate analysis. We performed a multivariate analysis to identify risk factors for patients treated between 2014 and 2018. Among 186 patients with enterococcal bacteremia, two groups included in the Kaplan–Meier analysis (E. faecalis (n = 88) and E. faecium (n = 94)) showed poor overall survival in the E. faecium group (HR: 1.92; 95% confidence interval: 1.01–3.66; p = 0.048). The median daily antibiotic cost per patient in the E. faecium group was significantly higher than that in the E. faecalis group ($23 ($13–$34) vs. $34 ($22–$58), p < 0.001). E. faecium strains were more frequently identified with previous ...
Cefazolin is an essential antibiotic used for treating bacteremia; in particular, it is recommend... more Cefazolin is an essential antibiotic used for treating bacteremia; in particular, it is recommended as a first-line agent for infections caused by methicillin-susceptible Staphylococcus aureus (MSSA). In March 2019, problems with a major antibiotic supplier caused a critical shortage of cefazolin in Japan; however, the impact of the cefazolin shortage on clinical outcomes remains unknown. This study aimed to evaluate the effect of the cefazolin shortage in patients with MSSA bacteremia. Data from 75 patients were compared between the pre-shortage (March 2018–January 2019, n = 39) and post-shortage (March 2019–January 2020, n = 36) periods. There were no significant differences in the demographic characteristics between the two groups, and the cefazolin shortage did not worsen clinical outcomes such as adverse drug reactions, treatment failure, and 30-day mortality. In the post-shortage group, ampicillin/sulbactam and benzylpenicillin were more frequently administered as alternative ...
BackgroundExtraction of mandibular third molars is one of the most commonly performed oral surgic... more BackgroundExtraction of mandibular third molars is one of the most commonly performed oral surgical procedures, and non-steroidal anti-inflammatory drugs (NSAIDs) are widely used for pain management. Oral administration of NSAIDs produces various adverse events such as gastrointestinal disorders, renal and hepatic dysfunction, and platelet dysfunction. Topical use of analgesics has been proposed as an alternative to oral and injectable medications to safely improve postoperative pain relief. We will conduct a single-center, placebo-controlled, double-blind, randomized crossover trial to assess the pain-relieving effect of an ibuprofen-containing gargle in patients undergoing extraction of mandibular third molars in comparison with a placebo gargle.MethodsThis study will be performed at Kobe University Hospital. Participants (n = 40) will be randomized equally to one of two groups. The IP group will receive ibuprofen gargle on postoperative day (POD) 1 and placebo gargle on POD 2. Th...
Proceedings for Annual Meeting of The Japanese Pharmacological Society, 2018
Background: Hand-foot skin reaction (HFSR) is a common side effect of multiple tyrosine kinase in... more Background: Hand-foot skin reaction (HFSR) is a common side effect of multiple tyrosine kinase inhibitors. HFSR can lead to dose reduction or the interruption of treatment due to decreasing QOL. The molecular cornification mechanisms of HFSR remain poorly understood. This study aimed to examine the effects of sunitinib on the expression of keratin 9 (KRT9), localized only in the terminally differentiated epidermis of the palmar and plantar skin. Methods: The expression of KRT9 in a 3D human epidermis tissue model comprising normal human epidermal keratinocytes were evaluated by immunohistochemical staining. The expression of KRT9 and Wnt/beta-catenin-related protein and mRNA in human epidermal keratinocytes (HaCaT) and human skin fibroblast (SF-TY) cell lines were evaluated using western blot and real-time qPCR analyses. Results and Discussion: HaCaT cells cultured in a lower Ca+ (0.2 mM) medium, but not in a higher Ca+ (2.0 mM) medium, exhibited an enhanced expression of the KRT9 protein and mRNA in a sunitinib concentration-dependent manner. Immunohistochemical imaging revealed that KRT9 expression in the 3D skin model was not enhanced by exposure to sunitinib. 3D skin model consists of a stratified epithelium harboring differentiated keratinocytes that are induced by high Ca+ concentration medium. These results suggested that the Ca+ concentration regulated the enhanced expression of KRT9 by sunitinib in keratinocytes. Moreover, HaCaT cells co-cultured with SF-TY cells exhibited markedly increased expression levels of KRT9 following sunitinib treatment, compared with HaCaT cells alone. SF-TY cells showed that sunitinib enhanced the mRNA levels of Wnt5a and DKK-1, which positively regulate KRT9 expression. Treating skin fibroblasts with sunitinib may increase the expression of KRT9 in keratinocytes via factors related to Wnt/beta-catenin signaling. Conclusions: The enhancement of KRT9 expression, regulated by Ca+ concentration and fibroblasts, was a mechanism of sunitinib-induced HFSR.
Journal of Pharmaceutical Health Care and Sciences, 2020
Background Oral mucositis frequently occurs in cancer patients treated with chemotherapy and chem... more Background Oral mucositis frequently occurs in cancer patients treated with chemotherapy and chemoradiotherapy (CRT). This study examined the safety and efficacy of ibuprofen gargle in healthy volunteers and patients with chemotherapy- and concomitant CRT-induced oral mucositis. Methods We enrolled healthy volunteers and patients with chemotherapy- and CRT-induced oral mucositis. In cohort I, single and multiple doses of ibuprofen gargle (0.6% or 1.0%) were administered to healthy volunteers on day 1 and days 4–10. In cohort II, multiple doses of ibuprofen gargle (0.6%) were administered to patients with complicated grade 2–3 oral mucositis based on the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. The primary endpoint of cohort I was the treatment-related adverse events (TRAEs) as defined by CTCAE version 4.0. The primary endpoint of cohort II was the change in the visual analogue scale (VAS) pain score from before to 15 min after gargle use on day 3. The inci...
Antimicrobial stewardship teams (ASTs) have been well-accepted in recent years; however, their cl... more Antimicrobial stewardship teams (ASTs) have been well-accepted in recent years; however, their clinical outcomes have not been fully investigated in urological patients. The purpose of this study was to evaluate the outcomes of intervention via a retrospective review of urological patients, as discussed in the AST meetings, who were treated with broad-spectrum antibiotics between 2014 and 2018 at the Department of Urology, Kobe University Hospital in Japan. Interventions were discussed in AST meetings for patients identified by pharmacists as having received inappropriate antibiotic therapy. The annual changes in numbers of inappropriate medications and culture submissions over five years at the urology department were statistically analyzed. Among 1,033 patients audited by pharmacists, inappropriate antibiotic therapy was found in 118 cases (11.4%). The numbers of inappropriate antibiotic use cases and of interventions for indefinite infections had significantly decreased during th...
American Journal of Physiology-Renal Physiology, 1997
We have previously shown that the p-aminohippurate (PAH) transport system in OK kidney epithelial... more We have previously shown that the p-aminohippurate (PAH) transport system in OK kidney epithelial cell line is under the regulatory control of protein kinase C. Parathyroid hormone (PTH) could activate protein kinase C, as well as protein kinase A, in OK cells. In the present study, the effect of PTH on PAH transport was studied in OK cells. PTH inhibited the transcellular transport of PAH from the basal to the apical side, as well as the accumulation of PAH in OK cells. Basolateral PAH uptake was inhibited by PTH in a dose- and time-dependent manner. Protein kinase A activators did not affect the transcellular transport or the accumulation of PAH. The PTH-induced inhibition of the accumulation of PAH was blocked by a protein kinase C inhibitor staurosporine. These results suggest that PTH inhibits the PAH transport in OK cells and that the messenger system mediated by protein kinase C, not protein kinase A, plays an important role in the regulation of PAH transport by PTH.
Iryo Yakugaku (Japanese Journal of Pharmaceutical Health Care and Sciences), 2018
Team-based learning (TBL) is an active learning method which has been designed to help students s... more Team-based learning (TBL) is an active learning method which has been designed to help students solve problems both by themselves and as a team. In this study, TBL was introduced in the journal club (gathering to read and discuss medical papers) for pharmacists, and its effectiveness was compared with that of a traditional lecture. The subjects, 29 pharmacists at Kobe University Hospital, were randomly allocated to the lecture group and TBL group. The pre-test was conducted two months before the journal club, and the post-tests were conducted immediately and one month after the journal club. There was no significant difference in the background data of the pharmacists between the lecture group and the TBL group. The score differences between the pre-test and the post-test immediately after the journal club were not significant (11.4 ± 2.3 points (mean ± SD) in the TBL group, 8.8 ± 4.2 points in the lecture group, P = 0.14). The post-test scores immediately after the journal club in the TBL group (19.6 ± 0.5 points) were significantly higher compared with those in the lecture group (17.8 ± 1.5 points) (P < 0.01), and the learning effect provided by TBL tended to be maintained one month after the TBL. In conclusion, TBL was an alternative method of the ordinal lecture and may be a useful learning method for pharmacists to read medical papers critically compared with the ordinal lecture.
Iryo Yakugaku (Japanese Journal of Pharmaceutical Health Care and Sciences), 2017
set up "Pharmaceutical Outpatient Clinics" for outpatients of the Departments of General Internal... more set up "Pharmaceutical Outpatient Clinics" for outpatients of the Departments of General Internal Medicine and Cardiovascular Surgery included in each ambulatory medical practice. Before the medical examination, the pharmacist in charge interviews each patient about medications in a separate room. Thereafter, the pharmacist participates in the medical examination for each patient, and intervenes in the prescription process by discussing with the medical doctor and each patient in the Departments of General Internal Medicine. In this study, the effects of the pharmacist＇s intervention in the "Pharmaceutical Outpatient Clinic" on the changes of prescribed drugs were evaluated. A total of 517 patients visited the "Pharmaceutical Outpatient Clinics" from May 2014 to March 2015. The pharmacist intervened in the prescriptions of drugs in patients visiting the "Pharmaceutical Outpatient Clinics" at a rate of 12.4％ (64 cases) and the doses were reduced at a rate of 5.6％ (29 cases), and both rates were significantly higher than those in patients without pharmacist＇s interventions (P < 0.01). No significant differences were observed in the frequency of adverse events due to the changed prescriptions with and without pharmacist＇s interventions (4.1％ vs 4.7％). The most frequent reason for the pharmacist＇s intervention was "an improvement of symptoms" in the outpatients of General Internal Medicine and "adaptation to the drug indication" in the outpatients of Cardiovascular Surgery, respectively. In conclusion, the "Pharmaceutical Outpatient Clinic," in cooperation with medical doctors, helps to promote appropriate drug usage.
PurposeWarfarin shows large inter- and intra-individual variabilities in its pharmacokinetics and... more PurposeWarfarin shows large inter- and intra-individual variabilities in its pharmacokinetics and pharmacodynamics. Sufficient understanding of factors affecting the response to warfarin is necessary to achieve improved outcomes for warfarin therapy. In this study, we evaluated effects of fasting on the anticoagulant properties of warfarin.MethodsWe conducted a retrospective observational study involving a total of 58 patients, who received cardiovascular surgeries and subsequent warfarin therapy. The effect of dietary intake on the anticoagulant properties with warfarin was assessed by measurement of the international normalized ratio of prothrombin time (PT-INR): the anticoagulant activities of warfarin were expressed as the warfarin sensitivity index (WSI). Additionally, fluctuations in WSI during the study period were obtained as differences between the maximum and minimum WSI.ResultsThe maximum PT-INR and WSI values were significantly higher for patients who were fasting for different reasons during the postoperative period than those in the group without reduced dietary intake. The differences between maximum and minimum WSI in the fasting group significantly increased compared with those in the groups with moderate or no reduced dietary intake. Meanwhile, effects of other markers of clinical conditions including the baseline Child-Pugh score and Charlson Comorbidity Index on WSI were not significant.ConclusionsOur results indicate that postoperative fasting was significantly associated with the anticoagulation activity of warfarin. In patients fasting for different reasons during the postoperative period, closer control of PT-INR values and warfarin adjustments may be required to avoid adverse effects such as bleeding in warfarin treatment.
Journal of Pharmaceutical Health Care and Sciences, 2018
Background: Risperidone is mainly metabolized by cytochrome P450 (CYP) 2D6 in the liver. The gene... more Background: Risperidone is mainly metabolized by cytochrome P450 (CYP) 2D6 in the liver. The gene encoding CYP2D6 is highly polymorphic. The average steady-state plasma concentration of risperidone active moiety is higher in the CYP2D6 intermediate metabolizers (IMs) compared with that in the extensive metabolizers (EMs). An association between drug-induced extrapyramidal symptoms scale (DIEPSS) score and CYP2D6 polymorphisms has not been reported to date. This study investigates the association of CYP2D6 polymorphisms with the severity of extrapyramidal symptoms in schizophrenia patients receiving risperidone therapy. Methods: Schizophrenia patients undergoing risperidone treatment were recruited for the study in the Kobe University Hospital. We evaluated extrapyramidal symptoms of schizophrenia using the DIEPSS. CYP2D6*10 and CYP2D6*14 were analyzed using TaqMan® assays, and CYP2D6*5 was analyzed using the long-PCR method. Patients with CYP2D6*1/*5, *1/*14, *5/*10, *10/*10, and *10/*14 were classified as IMs, and patients with CYP2D6*1/*1 and *1/*10 were classified as EMs. Patients with CYP2D6*5/*5, *5/*14, and *14/*14 were classified as poor metabolizers (PMs). Results: A total of 22 patients were included in the study. No patients were classified as PMs. The dose of risperidone (mg/day) was not significantly different between EMs (n = 15) and IMs (n = 7) (median with the interquartile range: 4.0 (2.0-6.0) vs. 4.0 (2.0-7.0) mg, p = 0.31). The age and disease duration of schizophrenia were not significantly different between the EMs and IMs. The DIEPSS score in the IMs was significantly higher than that in the EMs (median with the interquartile range: 5.0 (3.5-6.5) vs. 0.0 (0.0-3.0), p < 0.001). The multiple regression analysis showed that CYP2D6 IMs is a significant risk factor for the DIEPSS (p < 0.05). Conclusion: Special attentions should be paid to the onset of extrapyramidal symptoms in schizophrenia patients identified as CYP2D6 IM undergoing risperidone therapy.
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation, Jan 7, 2018
Mycophenolate mofetil (MMF) is a prodrug of mycophenolic acid (MPA) and is frequently used to pre... more Mycophenolate mofetil (MMF) is a prodrug of mycophenolic acid (MPA) and is frequently used to prevent acute graft-versus-host disease (aGVHD) in patients receiving hematopoietic stem cell transplantation (HSCT). However, optimal doses of MMF and target MPA concentrations in HSCT patients have not been defined. In this study, relationships between pharmacokinetic or pharmacodynamic markers of MPA and successful aGVHD prevention and neutrophil engraftment were evaluated to inform individualized MPA treatments in HSCT patients. We recruited 35 patients undergoing cord blood transplantation (CBT) who were treated with MMF. Area under the concentration-time curves from 0 to 24 hours (AUC) for free MPA and MPA acyl glucuronide (AcMPAG) at 1 week after the start of MMF treatments were significantly higher in patients with gastrointestinal (GI) aGVHD at stage ≥I than those at stage 0. Patients with faster neutrophil engraftment had higher free MPA AUC at 1 week after the start of MMF treatm...
To evaluate the long-term effects of comprehensive antibiotic stewardship programs (ASPs) on anti... more To evaluate the long-term effects of comprehensive antibiotic stewardship programs (ASPs) on antibiotic use, antimicrobial-resistant bacteria, and clinical outcomes. Before-after study. National university hospital with 934 beds. Implementation in March 2010 of a comprehensive ASPs including, among other strategies, weekly prospective audit and feedback with multidisciplinary collaboration. The primary outcome was the use of antipseudomonal antibiotics as measured by the monthly mean days of therapy per 1000 patient days each year. Secondary outcomes included overall antibiotic use and that of each antibiotic class, susceptibility of Pseudomonas aeruginosa, the proportion of patients isolated methicillin-resistant Staphylococcus aureus (MRSA) among all patients isolated S. aureus, the incidence of MRSA, and the 30-day mortality attributable to bacteremia. The mean monthly use of antipseudomonal antibiotics significantly decreased in 2011 and after as compared with 2009. Susceptibili...
Topiramate is a second-generation antiepileptic drug used as monotherapy and adjunctive therapy i... more Topiramate is a second-generation antiepileptic drug used as monotherapy and adjunctive therapy in adults and children with partial seizures. A population pharmacokinetic (PPK) analysis was performed to improve the topiramate dosage adjustment for individualized treatment. Patients whose steady-state serum concentration of topiramate was routinely monitored at Kyoto University Hospital from April 2012 to March 2013 were included in the model-building data. A nonlinear mixed effects modeling program was used to evaluate the influence of covariates on topiramate pharmacokinetics. The obtained PPK model was evaluated by internal model validations, including goodness-of-fit plots and prediction-corrected visual predictive checks, and was externally confirmed using the validation data from January 2015 to December 2015. A total of 177 steady-state serum concentrations from 93 patients were used for the model-building analysis. The patients' age ranged from 2 to 68 years, and body wei...
In our hospital, a full-time pharmacist specializing in antimicrobial therapy joined the newly la... more In our hospital, a full-time pharmacist specializing in antimicrobial therapy joined the newly launched antimicrobial stewardship team in May 2018, and started daily monitoring to optimize the use of broad-spectrum antimicrobials. For the medical staff to better understand antimicrobial therapy, the educational lectures were conducted four times after intervention. This study aimed to evaluate the impact of a full-time pharmacist's intervention on antimicrobial stewardship. The effects before (May-December 2017) and after the intervention period (May-December 2018) on antibiotic therapy and clinical outcomes were compared. The rate of blood culture collections before starting broad-spectrum antibiotics significantly increased after intervention (71% vs. 82%, p < 0.001), and initially prescribed broad-spectrum antibiotics were significantly de-escalated (55% vs. 78%, p = 0.004). A significant reduction in the monthly use of antipseudomonal antibiotics was observed (50.5 vs. 41.8 defined daily doses per 1000 patient-days, p = 0.01). The incidence of hospital-acquired Clostridioides difficile infection (HA-CDI) significantly decreased after intervention (1.12 vs. 0.54 cases per 10,000 patient-days, p = 0.033). The 30-day mortality rate did not change between the two periods (19.4% vs. 17.7%, p = 0.61). Our intervention ensured appropriate antimicrobial therapy and reduced the incidence of HA-CDI without worsening the clinical outcomes.
Our antimicrobial pharmacist-led intervention included: (a) a structured review of antibiotic pre... more Our antimicrobial pharmacist-led intervention included: (a) a structured review of antibiotic prescriptions; (b) educating prescribers on antimicrobial therapy; (c) monthly reporting of department-level rates of blood sampling for culture. Daily review began in May 2018 and was discontinued after 10 months; however, the other interventions were conducted throughout the study period. This study aimed to evaluate the sustained impact of pharmacist’s interventions on antimicrobial therapy and clinical outcomes between the baseline (May–December 2017), intervention (May–December 2018), and post-intervention (May–December 2019) periods. The rate of blood culture collections before starting antipseudomonal agent therapy was significantly increased from the baseline to post-intervention periods (71% vs. 85%, p < 0.001). Antipseudomonal agent therapy was more frequently de-escalated in the post-intervention period than in the baseline period (73% vs. 54%, p = 0.038). Total use of antipse...
AbstractPurpose. The purpose of this study was to clarify the mechanism of pharmacokinetic intera... more AbstractPurpose. The purpose of this study was to clarify the mechanism of pharmacokinetic interaction between cyclosporin A and probucol in clinical cases. Methods. The whole blood concentration of cyclosporin A was measured after oral administration of cyclosporin A with or without probucol in rats. Cyclosporin A was administered as three types of solutions: the contents of the conventional formulation (Sandimmun® capsule) diluted with corn oil and the contents of the new microemulsion preconcentrate formulation (Neoral® capsule) diluted with saline or corn oil. The solubility of cyclosporin A and another lipophilic agent tacrolimus in water with or without probucol was also measured. Results. The area under the blood concentration-time curve (AUC) after the administration of Sandimmun® (corn oil) and Neoral® (corn oil) was significantly decreased to 26% and 41% of the control by coadministration of probucol. However in the case of Neoral® (saline), it was unchanged. The terminal ...
Since 2014, several global and national guidelines have been introduced to address the problem of... more Since 2014, several global and national guidelines have been introduced to address the problem of antimicrobial resistance. We conducted a campaign in a tertiary hospital to promote appropriate quinolone use through educational lectures in 2018. The aim of this retrospective study was to evaluate the changes in the following: prescription characteristics, trend of oral quinolone use, and antibiotic susceptibility of bacteria from 2013 to 2020. Antimicrobial use was assessed as days of therapy per 1000 patient-days. We found a significant reduction in unnecessary antibiotic prescriptions between December 2013 and December 2020. Significant negative trends were detected in the use of quinolones over 8 years (outpatients, coefficient = −0.15655, p < 0.001; inpatients, coefficient = −0.004825, p = 0.0016). In particular, the monthly mean use of quinolones among outpatients significantly decreased by 11% from 2013 to 2014 (p < 0.05) and reduced further by 31% from 2017 to 2020 (p &...
The incidence of bacteremia caused by Enterococcus faecium, which is highly resistant to multiple... more The incidence of bacteremia caused by Enterococcus faecium, which is highly resistant to multiple antibiotics, is increasing in Japan. However, risk factors for the acquisition of E. faecium infection and mortality due to enterococcal bacteremia are not well known. We compared demographic, microbiological, and clinical characteristics using a Cox regression model and univariate analysis. We performed a multivariate analysis to identify risk factors for patients treated between 2014 and 2018. Among 186 patients with enterococcal bacteremia, two groups included in the Kaplan–Meier analysis (E. faecalis (n = 88) and E. faecium (n = 94)) showed poor overall survival in the E. faecium group (HR: 1.92; 95% confidence interval: 1.01–3.66; p = 0.048). The median daily antibiotic cost per patient in the E. faecium group was significantly higher than that in the E. faecalis group ($23 ($13–$34) vs. $34 ($22–$58), p < 0.001). E. faecium strains were more frequently identified with previous ...
Cefazolin is an essential antibiotic used for treating bacteremia; in particular, it is recommend... more Cefazolin is an essential antibiotic used for treating bacteremia; in particular, it is recommended as a first-line agent for infections caused by methicillin-susceptible Staphylococcus aureus (MSSA). In March 2019, problems with a major antibiotic supplier caused a critical shortage of cefazolin in Japan; however, the impact of the cefazolin shortage on clinical outcomes remains unknown. This study aimed to evaluate the effect of the cefazolin shortage in patients with MSSA bacteremia. Data from 75 patients were compared between the pre-shortage (March 2018–January 2019, n = 39) and post-shortage (March 2019–January 2020, n = 36) periods. There were no significant differences in the demographic characteristics between the two groups, and the cefazolin shortage did not worsen clinical outcomes such as adverse drug reactions, treatment failure, and 30-day mortality. In the post-shortage group, ampicillin/sulbactam and benzylpenicillin were more frequently administered as alternative ...
BackgroundExtraction of mandibular third molars is one of the most commonly performed oral surgic... more BackgroundExtraction of mandibular third molars is one of the most commonly performed oral surgical procedures, and non-steroidal anti-inflammatory drugs (NSAIDs) are widely used for pain management. Oral administration of NSAIDs produces various adverse events such as gastrointestinal disorders, renal and hepatic dysfunction, and platelet dysfunction. Topical use of analgesics has been proposed as an alternative to oral and injectable medications to safely improve postoperative pain relief. We will conduct a single-center, placebo-controlled, double-blind, randomized crossover trial to assess the pain-relieving effect of an ibuprofen-containing gargle in patients undergoing extraction of mandibular third molars in comparison with a placebo gargle.MethodsThis study will be performed at Kobe University Hospital. Participants (n = 40) will be randomized equally to one of two groups. The IP group will receive ibuprofen gargle on postoperative day (POD) 1 and placebo gargle on POD 2. Th...
Proceedings for Annual Meeting of The Japanese Pharmacological Society, 2018
Background: Hand-foot skin reaction (HFSR) is a common side effect of multiple tyrosine kinase in... more Background: Hand-foot skin reaction (HFSR) is a common side effect of multiple tyrosine kinase inhibitors. HFSR can lead to dose reduction or the interruption of treatment due to decreasing QOL. The molecular cornification mechanisms of HFSR remain poorly understood. This study aimed to examine the effects of sunitinib on the expression of keratin 9 (KRT9), localized only in the terminally differentiated epidermis of the palmar and plantar skin. Methods: The expression of KRT9 in a 3D human epidermis tissue model comprising normal human epidermal keratinocytes were evaluated by immunohistochemical staining. The expression of KRT9 and Wnt/beta-catenin-related protein and mRNA in human epidermal keratinocytes (HaCaT) and human skin fibroblast (SF-TY) cell lines were evaluated using western blot and real-time qPCR analyses. Results and Discussion: HaCaT cells cultured in a lower Ca+ (0.2 mM) medium, but not in a higher Ca+ (2.0 mM) medium, exhibited an enhanced expression of the KRT9 protein and mRNA in a sunitinib concentration-dependent manner. Immunohistochemical imaging revealed that KRT9 expression in the 3D skin model was not enhanced by exposure to sunitinib. 3D skin model consists of a stratified epithelium harboring differentiated keratinocytes that are induced by high Ca+ concentration medium. These results suggested that the Ca+ concentration regulated the enhanced expression of KRT9 by sunitinib in keratinocytes. Moreover, HaCaT cells co-cultured with SF-TY cells exhibited markedly increased expression levels of KRT9 following sunitinib treatment, compared with HaCaT cells alone. SF-TY cells showed that sunitinib enhanced the mRNA levels of Wnt5a and DKK-1, which positively regulate KRT9 expression. Treating skin fibroblasts with sunitinib may increase the expression of KRT9 in keratinocytes via factors related to Wnt/beta-catenin signaling. Conclusions: The enhancement of KRT9 expression, regulated by Ca+ concentration and fibroblasts, was a mechanism of sunitinib-induced HFSR.
Journal of Pharmaceutical Health Care and Sciences, 2020
Background Oral mucositis frequently occurs in cancer patients treated with chemotherapy and chem... more Background Oral mucositis frequently occurs in cancer patients treated with chemotherapy and chemoradiotherapy (CRT). This study examined the safety and efficacy of ibuprofen gargle in healthy volunteers and patients with chemotherapy- and concomitant CRT-induced oral mucositis. Methods We enrolled healthy volunteers and patients with chemotherapy- and CRT-induced oral mucositis. In cohort I, single and multiple doses of ibuprofen gargle (0.6% or 1.0%) were administered to healthy volunteers on day 1 and days 4–10. In cohort II, multiple doses of ibuprofen gargle (0.6%) were administered to patients with complicated grade 2–3 oral mucositis based on the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. The primary endpoint of cohort I was the treatment-related adverse events (TRAEs) as defined by CTCAE version 4.0. The primary endpoint of cohort II was the change in the visual analogue scale (VAS) pain score from before to 15 min after gargle use on day 3. The inci...
Antimicrobial stewardship teams (ASTs) have been well-accepted in recent years; however, their cl... more Antimicrobial stewardship teams (ASTs) have been well-accepted in recent years; however, their clinical outcomes have not been fully investigated in urological patients. The purpose of this study was to evaluate the outcomes of intervention via a retrospective review of urological patients, as discussed in the AST meetings, who were treated with broad-spectrum antibiotics between 2014 and 2018 at the Department of Urology, Kobe University Hospital in Japan. Interventions were discussed in AST meetings for patients identified by pharmacists as having received inappropriate antibiotic therapy. The annual changes in numbers of inappropriate medications and culture submissions over five years at the urology department were statistically analyzed. Among 1,033 patients audited by pharmacists, inappropriate antibiotic therapy was found in 118 cases (11.4%). The numbers of inappropriate antibiotic use cases and of interventions for indefinite infections had significantly decreased during th...
American Journal of Physiology-Renal Physiology, 1997
We have previously shown that the p-aminohippurate (PAH) transport system in OK kidney epithelial... more We have previously shown that the p-aminohippurate (PAH) transport system in OK kidney epithelial cell line is under the regulatory control of protein kinase C. Parathyroid hormone (PTH) could activate protein kinase C, as well as protein kinase A, in OK cells. In the present study, the effect of PTH on PAH transport was studied in OK cells. PTH inhibited the transcellular transport of PAH from the basal to the apical side, as well as the accumulation of PAH in OK cells. Basolateral PAH uptake was inhibited by PTH in a dose- and time-dependent manner. Protein kinase A activators did not affect the transcellular transport or the accumulation of PAH. The PTH-induced inhibition of the accumulation of PAH was blocked by a protein kinase C inhibitor staurosporine. These results suggest that PTH inhibits the PAH transport in OK cells and that the messenger system mediated by protein kinase C, not protein kinase A, plays an important role in the regulation of PAH transport by PTH.
Iryo Yakugaku (Japanese Journal of Pharmaceutical Health Care and Sciences), 2018
Team-based learning (TBL) is an active learning method which has been designed to help students s... more Team-based learning (TBL) is an active learning method which has been designed to help students solve problems both by themselves and as a team. In this study, TBL was introduced in the journal club (gathering to read and discuss medical papers) for pharmacists, and its effectiveness was compared with that of a traditional lecture. The subjects, 29 pharmacists at Kobe University Hospital, were randomly allocated to the lecture group and TBL group. The pre-test was conducted two months before the journal club, and the post-tests were conducted immediately and one month after the journal club. There was no significant difference in the background data of the pharmacists between the lecture group and the TBL group. The score differences between the pre-test and the post-test immediately after the journal club were not significant (11.4 ± 2.3 points (mean ± SD) in the TBL group, 8.8 ± 4.2 points in the lecture group, P = 0.14). The post-test scores immediately after the journal club in the TBL group (19.6 ± 0.5 points) were significantly higher compared with those in the lecture group (17.8 ± 1.5 points) (P < 0.01), and the learning effect provided by TBL tended to be maintained one month after the TBL. In conclusion, TBL was an alternative method of the ordinal lecture and may be a useful learning method for pharmacists to read medical papers critically compared with the ordinal lecture.
Iryo Yakugaku (Japanese Journal of Pharmaceutical Health Care and Sciences), 2017
set up "Pharmaceutical Outpatient Clinics" for outpatients of the Departments of General Internal... more set up "Pharmaceutical Outpatient Clinics" for outpatients of the Departments of General Internal Medicine and Cardiovascular Surgery included in each ambulatory medical practice. Before the medical examination, the pharmacist in charge interviews each patient about medications in a separate room. Thereafter, the pharmacist participates in the medical examination for each patient, and intervenes in the prescription process by discussing with the medical doctor and each patient in the Departments of General Internal Medicine. In this study, the effects of the pharmacist＇s intervention in the "Pharmaceutical Outpatient Clinic" on the changes of prescribed drugs were evaluated. A total of 517 patients visited the "Pharmaceutical Outpatient Clinics" from May 2014 to March 2015. The pharmacist intervened in the prescriptions of drugs in patients visiting the "Pharmaceutical Outpatient Clinics" at a rate of 12.4％ (64 cases) and the doses were reduced at a rate of 5.6％ (29 cases), and both rates were significantly higher than those in patients without pharmacist＇s interventions (P < 0.01). No significant differences were observed in the frequency of adverse events due to the changed prescriptions with and without pharmacist＇s interventions (4.1％ vs 4.7％). The most frequent reason for the pharmacist＇s intervention was "an improvement of symptoms" in the outpatients of General Internal Medicine and "adaptation to the drug indication" in the outpatients of Cardiovascular Surgery, respectively. In conclusion, the "Pharmaceutical Outpatient Clinic," in cooperation with medical doctors, helps to promote appropriate drug usage.
PurposeWarfarin shows large inter- and intra-individual variabilities in its pharmacokinetics and... more PurposeWarfarin shows large inter- and intra-individual variabilities in its pharmacokinetics and pharmacodynamics. Sufficient understanding of factors affecting the response to warfarin is necessary to achieve improved outcomes for warfarin therapy. In this study, we evaluated effects of fasting on the anticoagulant properties of warfarin.MethodsWe conducted a retrospective observational study involving a total of 58 patients, who received cardiovascular surgeries and subsequent warfarin therapy. The effect of dietary intake on the anticoagulant properties with warfarin was assessed by measurement of the international normalized ratio of prothrombin time (PT-INR): the anticoagulant activities of warfarin were expressed as the warfarin sensitivity index (WSI). Additionally, fluctuations in WSI during the study period were obtained as differences between the maximum and minimum WSI.ResultsThe maximum PT-INR and WSI values were significantly higher for patients who were fasting for different reasons during the postoperative period than those in the group without reduced dietary intake. The differences between maximum and minimum WSI in the fasting group significantly increased compared with those in the groups with moderate or no reduced dietary intake. Meanwhile, effects of other markers of clinical conditions including the baseline Child-Pugh score and Charlson Comorbidity Index on WSI were not significant.ConclusionsOur results indicate that postoperative fasting was significantly associated with the anticoagulation activity of warfarin. In patients fasting for different reasons during the postoperative period, closer control of PT-INR values and warfarin adjustments may be required to avoid adverse effects such as bleeding in warfarin treatment.
Journal of Pharmaceutical Health Care and Sciences, 2018
Background: Risperidone is mainly metabolized by cytochrome P450 (CYP) 2D6 in the liver. The gene... more Background: Risperidone is mainly metabolized by cytochrome P450 (CYP) 2D6 in the liver. The gene encoding CYP2D6 is highly polymorphic. The average steady-state plasma concentration of risperidone active moiety is higher in the CYP2D6 intermediate metabolizers (IMs) compared with that in the extensive metabolizers (EMs). An association between drug-induced extrapyramidal symptoms scale (DIEPSS) score and CYP2D6 polymorphisms has not been reported to date. This study investigates the association of CYP2D6 polymorphisms with the severity of extrapyramidal symptoms in schizophrenia patients receiving risperidone therapy. Methods: Schizophrenia patients undergoing risperidone treatment were recruited for the study in the Kobe University Hospital. We evaluated extrapyramidal symptoms of schizophrenia using the DIEPSS. CYP2D6*10 and CYP2D6*14 were analyzed using TaqMan® assays, and CYP2D6*5 was analyzed using the long-PCR method. Patients with CYP2D6*1/*5, *1/*14, *5/*10, *10/*10, and *10/*14 were classified as IMs, and patients with CYP2D6*1/*1 and *1/*10 were classified as EMs. Patients with CYP2D6*5/*5, *5/*14, and *14/*14 were classified as poor metabolizers (PMs). Results: A total of 22 patients were included in the study. No patients were classified as PMs. The dose of risperidone (mg/day) was not significantly different between EMs (n = 15) and IMs (n = 7) (median with the interquartile range: 4.0 (2.0-6.0) vs. 4.0 (2.0-7.0) mg, p = 0.31). The age and disease duration of schizophrenia were not significantly different between the EMs and IMs. The DIEPSS score in the IMs was significantly higher than that in the EMs (median with the interquartile range: 5.0 (3.5-6.5) vs. 0.0 (0.0-3.0), p < 0.001). The multiple regression analysis showed that CYP2D6 IMs is a significant risk factor for the DIEPSS (p < 0.05). Conclusion: Special attentions should be paid to the onset of extrapyramidal symptoms in schizophrenia patients identified as CYP2D6 IM undergoing risperidone therapy.
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation, Jan 7, 2018
Mycophenolate mofetil (MMF) is a prodrug of mycophenolic acid (MPA) and is frequently used to pre... more Mycophenolate mofetil (MMF) is a prodrug of mycophenolic acid (MPA) and is frequently used to prevent acute graft-versus-host disease (aGVHD) in patients receiving hematopoietic stem cell transplantation (HSCT). However, optimal doses of MMF and target MPA concentrations in HSCT patients have not been defined. In this study, relationships between pharmacokinetic or pharmacodynamic markers of MPA and successful aGVHD prevention and neutrophil engraftment were evaluated to inform individualized MPA treatments in HSCT patients. We recruited 35 patients undergoing cord blood transplantation (CBT) who were treated with MMF. Area under the concentration-time curves from 0 to 24 hours (AUC) for free MPA and MPA acyl glucuronide (AcMPAG) at 1 week after the start of MMF treatments were significantly higher in patients with gastrointestinal (GI) aGVHD at stage ≥I than those at stage 0. Patients with faster neutrophil engraftment had higher free MPA AUC at 1 week after the start of MMF treatm...
To evaluate the long-term effects of comprehensive antibiotic stewardship programs (ASPs) on anti... more To evaluate the long-term effects of comprehensive antibiotic stewardship programs (ASPs) on antibiotic use, antimicrobial-resistant bacteria, and clinical outcomes. Before-after study. National university hospital with 934 beds. Implementation in March 2010 of a comprehensive ASPs including, among other strategies, weekly prospective audit and feedback with multidisciplinary collaboration. The primary outcome was the use of antipseudomonal antibiotics as measured by the monthly mean days of therapy per 1000 patient days each year. Secondary outcomes included overall antibiotic use and that of each antibiotic class, susceptibility of Pseudomonas aeruginosa, the proportion of patients isolated methicillin-resistant Staphylococcus aureus (MRSA) among all patients isolated S. aureus, the incidence of MRSA, and the 30-day mortality attributable to bacteremia. The mean monthly use of antipseudomonal antibiotics significantly decreased in 2011 and after as compared with 2009. Susceptibili...
Topiramate is a second-generation antiepileptic drug used as monotherapy and adjunctive therapy i... more Topiramate is a second-generation antiepileptic drug used as monotherapy and adjunctive therapy in adults and children with partial seizures. A population pharmacokinetic (PPK) analysis was performed to improve the topiramate dosage adjustment for individualized treatment. Patients whose steady-state serum concentration of topiramate was routinely monitored at Kyoto University Hospital from April 2012 to March 2013 were included in the model-building data. A nonlinear mixed effects modeling program was used to evaluate the influence of covariates on topiramate pharmacokinetics. The obtained PPK model was evaluated by internal model validations, including goodness-of-fit plots and prediction-corrected visual predictive checks, and was externally confirmed using the validation data from January 2015 to December 2015. A total of 177 steady-state serum concentrations from 93 patients were used for the model-building analysis. The patients' age ranged from 2 to 68 years, and body wei...
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