Publications by authors named "Tetsuya Yagi"

110 Publications

Three-day regimen of oseltamivir for post-exposure prophylaxis of influenza in hospital wards: a study protocol for a prospective, multi-center, single-arm trial.

BMC Infect Dis 2021 Aug 30;21(1):887. Epub 2021 Aug 30.

Center for Regional Medicine, Gifu University School of Medicine, 1-1 Yanagido, Gifu, Gifu, 501-1194, Japan.

Background: In a previous retrospective observational study, a 3-day regimen of oseltamivir as post-exposure prophylaxis (PEP) for preventing transmission of influenza in wards was shown to be comparable to 7- to 10-day regimens provided index cases were immediately separated from close contacts. In order to confirm the efficacy of a 3-day regimen, we started to conduct a prospective, multi-center, single-arm trial.

Methods: This study is a prospective, multi-center, single-arm study designed by the Sectional Meeting of Clinical Study, Japan Infection Prevention and Control Conference for National and Public University Hospitals. Index patients with influenza are prescribed a neuraminidase inhibitor and are discharged immediately or transferred to isolation rooms. The close contacts are given oseltamivir as 75 mg capsules once daily for adults or 2 mg/kg (maximum of 75 mg) once daily for children for 3 days as PEP. All close contacts are monitored for development of influenza for 7 days after starting PEP.

Discussion: A 3-day regimen of oseltamivir as PEP has advantages over 7- to 10-day regimens in terms of costs, medication adherence and adverse effects. Trial registration The Institutional Review Board of Hokkaido University Hospital for Clinical Research, 015-0518, registered on November 11, 2016. UMIN Clinical Trials Registry, UMIN000024458, disclosed on October 31, 2016. https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000027881 . Japan Registry of Clinical Trials, jRCTs011180015, disclosed on March 14, 2019. https://jrct.niph.go.jp/latest-detail/jRCTs011180015.
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http://dx.doi.org/10.1186/s12879-021-06602-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8407088PMC
August 2021

Molecular epidemiology of Enterobacter cloacae complex isolates with reduced carbapenem susceptibility recovered by blood culture.

Jpn J Infect Dis 2021 Jun 30. Epub 2021 Jun 30.

Department of Bacteriology, Nagoya University Graduate School of Medicine, Japan.

The Enterobacter cloacae complex (ECC) is one of the most common causes of bacteremia and leads to poor clinical outcomes. The aim of this study was to clarify the antimicrobial susceptibility profiles and genetic backgrounds of non-carbapenemase-producing reduced-carbapenem-susceptible (RCS) ECC blood isolates in Japan using agar dilution antimicrobial susceptibility testing, whole-genome sequencing, and quantitative polymerase chain reaction for assays of ampC, ompC and ompF transcripts. Forty-two ECC blood isolates were categorized into RCS and carbapenem-susceptible groups based on imipenem minimum inhibitory concentration. RCS ECC blood isolates belonged to distinct species and sequence types and produced varying class C β-lactamases. The E. roggenkampii, E. asburiae, and E. bugandensis isolates belonged only to the RCS group. Some E. hormaecheii ssp. steigerwaltii isolates of the RCS group exhibited AmpC overexpression caused by amino acid substitutions in AmpD and AmpR along with ompF gene downregulation. These findings suggest that non-carbapenemase-producing RCS ECC blood isolates are genetically diverse.
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http://dx.doi.org/10.7883/yoken.JJID.2021.141DOI Listing
June 2021

Trends in Antipseudomonal Agent Use Based on the 2006 to 2015 Sales Data in Japan.

Biol Pharm Bull 2021 ;44(6):816-821

Department of Clinical Pharmacoepidemiology, Kyoto Pharmaceutical University.

Pseudomonas aeruginosa resistance is a major issue worldwide. Drug resistance is related to inappropriate antibiotic use. Because antipseudomonal agents have a wide spectrum, they must be used appropriately. The purpose of this study was to clarify the trends in antipseudomonal agent use in Japan based on sales data from 2006 to 2015. The total antipseudomonal agent use was increased significantly (r = 0.10, P = 0.00040). The proportion of fluoroquinolones use was the highest throughout the year, accounting for 88.6-91.4%. The use of piperacillin/tazobactam significantly increased. The increased use of these drugs may be due to the launch of higher doses and additional indications. On the other hand, for antipseudomonal agents, parenteral carbapenems use was 2.7-3.7%, but it has remained unchanged over the years. In Japan, permit and notification systems have been introduced to prevent the inappropriate use of parenteral carbapenems in medical institutions. It was speculated that these efforts suppressed the inappropriate use of parenteral carbapenems. This study clarified the trend of antipseudomonal agent use in Japan from 2006 to 2015. It is important to continue monitoring antipseudomonal agents use to conduct appropriate antimicrobial resistance measures.
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http://dx.doi.org/10.1248/bpb.b21-00004DOI Listing
January 2021

Bursitis, Bacteremia, and Disseminated Infection of Mycobacteroides (Mycobacterium) abscessus subsp. massiliense.

Intern Med 2021 Sep 29;60(18):3041-3045. Epub 2021 Mar 29.

Department of Infectious Diseases, Nagoya University Hospital, Japan.

We herein report a 59-year-old woman with a 2-year history of chronic bursitis of the hand who took 50 mg/day prednisolone for several autoimmune diseases. Mycobacteroides abscessus subsp. massiliense was isolated from the abscess and blood culture. Combination therapy (imipenem/cilastatin, amikacin, and clarithromycin) was administered for a month. Two months later, M. massiliense was detected from a blood culture again, and disseminated lesions were found. Clarithromycin and sitafloxacin were administered following eight weeks of the same regimen. Six months after the diagnosis, M. massiliense was isolated from a blood culture, and she expired due to multiple organ failure.
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http://dx.doi.org/10.2169/internalmedicine.6189-20DOI Listing
September 2021

Trends of the Use of Anti-methicillin-Resistant Staphylococcus aureus Agents in Japan Based on Sales Data from 2006 to 2015.

Biol Pharm Bull 2020 ;43(12):1906-1910

Department of Clinical Pharmacoepidemiology, Kyoto Pharmaceutical University.

Patterns of the use of anti-methicillin-resistant Staphylococcus aureus (MRSA) agents in Japan might be influenced by the launch of new anti-MRSA agents, the publication of relevant guidelines, and the increase in the number of generic medicines. However, as anti-MRSA agents are included in multiple anatomical therapeutic chemical classifications, such as glycopeptides and aminoglycosides, the trends of the use of individual anti-MRSA agents remain unclear. Here, we aimed to clarify the trends of anti-MRSA agent use in Japan from 2006 to 2015 based on sales data. Total anti-MRSA agent use was found to have significantly increased from 2006 to 2015 (P = 0.027, r = 0.00022). Individual trends for vancomycin (VCM), daptomycin, and linezolid (LZD) use showed significant increases, while those for arbekacin (ABK) and teicoplanin (TEIC) showed decreases. In addition, oral LZD use significantly increased, while there was no significant change in intravenous LZD use. The ratio of oral LZD use to total LZD use increased from 25.5% in 2006 to 39.9% in 2015. Meanwhile, TEIC and ABK use decreased, while VCM use increased, following the launch of generic medicines. These results might reflect the status of guideline compliance, the launch of new anti-MRSA agents, and the decline in the sales promotion of the original medicines. It is extremely important to investigate trends for the use of not only different antibiotic groups but also individual antibiotics to develop and implement antimicrobial resistance countermeasures.
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http://dx.doi.org/10.1248/bpb.b20-00605DOI Listing
August 2021

Number of concomitant drugs with thrombocytopenic adverse effects and the extent inflammatory response resolution are risk factors for thrombocytopenia in patients treated with linezolid for more than 14 days.

Nagoya J Med Sci 2020 Aug;82(3):407-414

Department of Infectious Diseases, Nagoya University Hospital, Nagoya, Japan.

Prolonged treatment with linezolid (LZD) is known to cause thrombocytopenia. However, some patients do not develop thrombocytopenia despite long-term administration of LZD. To determine the risk factors for LZD-associated thrombocytopenia in patients undergoing long-term LZD therapy, we conducted a retrospective cohort study among 212 patients receiving LZD treatment between December 2011 and June 2014 at a tertiary referral university hospital in Nagoya, Japan. Of the 217 patients who received LZD, 37 were treated with LZD for more than 14 days and were enrolled in the study. We compared data on demographic characteristics, underlying disease, microbiology, concomitant drugs, and laboratory tests between the thrombocytopenia group and the non-thrombocytopenia group. Thrombocytopenia was defined as having a platelet count < 100 × 10/μL or a ≥ 50% reduction in platelet count compared to baseline. Among the 37 patients who received LZD for more than 14 days, 17 (45.9%) developed thrombocytopenia. Multivariate logistic regression revealed that both the number of concomitant drugs with thrombocytopenic adverse effects (DTADE) (OR = 1.690; 95% CI = 1.037-2.754; = 0.035) and a small decrease in the level of C-reactive protein (CRP) 14 days post-administration (OR = 0.965; 95% CI = 0.939-0.993; = 0.013) were associated with thrombocytopenia during long-term LZD therapy. Therefore, the number of concomitant DTADE and a small decrease in CRP on the 14th day of treatment were key factors for the appearance of LZD-associated thrombocytopenia in patients with long-term LZD therapy. Our findings may be useful for preventing thrombocytopenia in patients treated with LZD for longer than 14 days.
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http://dx.doi.org/10.18999/nagjms.82.3.407DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7548242PMC
August 2020

Efficacy of favipiravir for an end stage renal disease patient on maintenance hemodialysis infected with novel coronavirus disease 2019.

CEN Case Rep 2021 02 17;10(1):126-131. Epub 2020 Sep 17.

Department of Nephrology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.

Background: Novel coronavirus disease 2019 (COVID-19) refers to infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pathogen, and has spread to pandemic levels since its inception in December 2019. While several risk factors for severe presentation have been identified, the clinical course for end-stage renal disease (ESRD) patients on maintenance hemodialysis with COVID-19 has been unclear. Previous studies have revealed that some antiviral agents may be effective against COVID-19 in the general population, but the pharmacokinetics and pharmacodynamics of these agents in ESRD patients remain under investigation. Favipiravir, an antiviral agent developed for treatment of influenza, is one candidate treatment for COVID-19, but suitable dosages for patients with renal insufficiency are unknown. Here we provide a first report on the efficacy of favipiravir in a patient with ESRD undergoing hemodialysis.

Case Presentation: The case involved a 52-year-old woman with COVID-19 who had been undergoing maintenance hemodialysis three times a week for 3 years due to diabetic nephropathy. She had initially been treated with lopinavir/ritonavir and ciclesonide for 5 days, but developed severe pneumonia requiring invasive positive-pressure ventilation. Those antiviral agents were subsequently switched to favipiravir. She recovered gradually, and after 2 weeks was extubated once the viral load of SARS-CoV-2 fell below the limit of detection. Although concentrations of several biliary enzymes were elevated, no major adverse events were observed.

Conclusion: Favipiravir may be an effective option for the treatment of COVID-19-infected patients with ESRD.
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http://dx.doi.org/10.1007/s13730-020-00534-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7494976PMC
February 2021

Impact of antimicrobial stewardship fee on prescribing for Japanese pediatric patients with upper respiratory infections.

BMC Health Serv Res 2020 May 11;20(1):399. Epub 2020 May 11.

Antimicrobial Resistance Clinical Reference Center, Disease Control and Prevention Center, National Center for Global Health and Medicine, Tokyo, Japan.

Background: In 2018, the Japanese medical reimbursement system was revised to introduce a fee for the implementation of an antimicrobial stewardship (AS) fee for pediatric patients. The purpose of this study was to evaluate physicians' prescription behavior following this revision.

Methods: We conducted a retrospective observational study from January 1, 2017 to September 30, 2018 of pediatric (< 15 years) outpatients with upper respiratory tract infections (URIs). To assess the pattern of antibiotic prescription for the treatment of pediatric URIs before and after the introduction of the AS fee, we extracted data on pediatric URIs, diagnosed during the study period. Patients were divided based on whether medical facilities claimed AS fees. We defined antibiotic use as the number of antibiotics prescribed, and evaluated the proportion of each class to the total number of antibiotics prescribed. We also recorded the number of medical facilities that each patient visited during the study period.

Results: The frequency of antibiotic prescription decreased after AS fee implementation, regardless of whether the facility claimed the AS fee, but tended to be lower in facilities that claimed the fee. Additionally, the frequency of antibiotic prescription decreased in all age groups. Despite the reduced frequency of antibiotic prescription, consultation behavior did not change.

Conclusions: The AS fee system, which compensates physicians for limiting antibiotic prescriptions, helped to reduce unnecessary antibiotic prescription and is thus a potentially effective measure against antimicrobial resistance.
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http://dx.doi.org/10.1186/s12913-020-05288-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7212615PMC
May 2020

The Trend for Antibiotic Use for Clostridioides (Clostridium) difficile Infection in Japan.

Biol Pharm Bull 2020 ;43(4):693-696

AMR Clinical Reference Center, Disease Control and Prevention Center, National Center for Global Health and Medicine.

In Japan, there is no national surveillance study of Clostridioides (Clostridium) difficile infection (CDI), and details about the epidemiology and treatment status of CDI are unknown. Additionally, clinical practice guidelines (CPGs) for CDI are published by four different institutions. All CPGs recommend that the antimicrobials, vancomycin (VCM) and metronidazole (MNZ), should be selected according to disease severity. However, the trends for VCM and MNZ use in Japan remain unclear. Therefore, this study was aimed at clarifying the secular trends for VCM and MNZ use based on sales data from 2006 to 2015 and discussing its impact on CDI status and drug costs. This is the first study to clarify the antibiotic use trends for CDI treatment. We found that the total use increased over time (r = 0.0013, P < 0.0001). While VCM use significantly decreased (r = -0.0003, P = 0.0002), MNZ use increased (r = 0.0017, P < 0.0001). These results show that although treatment for CDI was in line with CPGs, CDI incidence might be on an increasing trend. Additionally, despite the increased total use, the total drug costs decreased by 55% ($ 25 million) from 2006 to 2015. It was also surmised that CDI treatment in compliance with CPGs would lead to a reduction in drug costs. Hence, to understand the epidemiology of CDI, it is important to continuously investigate the use of drugs used for CDI therapy.
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http://dx.doi.org/10.1248/bpb.b19-01000DOI Listing
November 2020

[Successful treatment of pre-engraftment disseminated fusariosis with high-dose liposomal amphotericin B in a cord blood transplant recipient].

Rinsho Ketsueki 2019 ;60(12):1641-1646

Department of Hematology and Oncology, Nagoya University Graduate School of Medicine.

A 47-year-old man with acute myeloid leukemia and myelodysplastic-related changes relapsed after an allogenic bone marrow transplant and received a cord blood transplant as salvage therapy. The patient developed febrile neutropenia that was resistant to broad-spectrum antibiotics and multiple, painful, nodular skin lesions on his trunk and extremities before engraftment. A skin biopsy and blood culture found mold, and the subsequent microscopic examination, mass spectrometry, and DNA sequencing of the fungal colonies identified Fusarium solani. The patient's fever and skin lesions began to improve with the administration of liposomal amphotericin B at 5 mg/kg/day. Neutrophilic engraftment occurred on day 19. Stage 3 acute skin graft-versus-host disease was cured by the application of topical steroid. Unexpectedly, a change from liposomal amphotericin B to voriconazole on day 38 exacerbated the Fusarium infection. The Fusarium infection was finally cured by the administration of liposomal amphotericin B for a total of 19 weeks. Neutrophilic engraftment, an immediate definitive diagnosis, the sufficient and long-term administration of appropriate antifungal medication, and avoidance of the systemic administration of steroids might have contributed to the successful outcome of this patient.
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http://dx.doi.org/10.11406/rinketsu.60.1641DOI Listing
January 2020

Detection of bacteria in blood circulation in patients receiving cancer chemotherapy.

Int J Clin Oncol 2020 Jan 12;25(1):210-215. Epub 2019 Aug 12.

Department of Clinical Oncology and Chemotherapy, Nagoya University Hospital, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8560, Aichi, Japan.

Introduction: Bacterial translocation, in which intestinal bacteria pass through the intestinal wall, enter the blood circulation, and spread to other sites of the body, is thought to cause bacteremia and sometimes febrile neutropenia (FN) in patients who receive cancer chemotherapy.

Materials And Methods: We collected blood samples from 39 patients with various cancers at baseline and after chemotherapy began (during chemotherapy) and explored how frequently bacteria could be detected in the blood using a highly-sensitive, bacterial rRNA-targeted reverse transcription quantitative polymerase chain reaction (PCR) assay.

Results: Bacterial traces, typically Escherichia coli and Enterobacter spp., were detected in 10 patients (25.6%) at baseline and 11 patients (28.2%) during chemotherapy. The bacterial traces were positive either at baseline or during chemotherapy in 3 (60%) of 5 patients who had FN, and 6 (46%) of 13 patients aged 65 years or older.

Conclusion: These findings support the notion that bacterial translocation occurs in patients with cancer regardless of whether they receive chemotherapy and can lead to the development of FN and other treatment-related infections.
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http://dx.doi.org/10.1007/s10147-019-01521-yDOI Listing
January 2020

Molecular epidemiological analysis and risk factors for acquisition of carbapenemase-producing complex in a Japanese university hospital.

Antimicrob Resist Infect Control 2019 24;8:126. Epub 2019 Jul 24.

1Department of Infectious Diseases, Nagoya University Hospital, 65 Tsurumai, Nagoya, Aichi 466-0065 Japan.

Background: To clarify the molecular epidemiology of carbapenem-resistant complex (CREC) and the risk factors for acquisition of carbapenemase-producing complex (CPEC).

Methods: Using clinical CREC isolates detected in a Japanese university hospital over 4 years, carbapenemase production was screened with phenotypic methods. Carbapenemase genes were analysed by PCR and sequencing. Molecular epidemiological analyses were conducted with repetitive extragenic palindromic (REP)-PCR and multilocus sequence typing (MLST). CRECs were identified to the subspecies level by sequencing. Whole-genome sequencing of plasmids was conducted. A case-control study was performed to identify risk factors for acquisition of CPEC among patients with CREC.

Results: Thirty-nine CRECs including 20 CPECs carrying were identified. Patients with CPEC had longer hospital stay before detection (26.5 days vs. 12 days,  = 0.008), a urinary catheter (odds ratio [OR], 5.36; 95% confidence interval [CI], 1.14-30.9;  = 0.023), or intubation (OR, 7.53; 95% CI, 1.47-53.8;  = 0.008) compared to patients without CPEC. Four genetically closely related CPEC clusters were observed, which showed that three of four CPEC clusters corresponded to (ST 53), subsp. (ST 113 and ST 1047) and subsp. (ST 513) by MLST and sequencing. Seven representative plasmids shared structures with class I integron containing and IncHI2A replicon type.

Conclusions: A longer hospital stay, presence of a urinary catheter, and intubation are risk factors for CPEC acquisition. In addition to horizontal transmission of genetically indistinguishable CPECs, IncHI2A plasmid carrying appeared to be transferred among genetically different ECs.
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http://dx.doi.org/10.1186/s13756-019-0578-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6657070PMC
June 2020

Focal activation of neuronal circuits induced by microstimulation in the visual cortex.

J Neural Eng 2019 06 28;16(3):036007. Epub 2019 Feb 28.

Division of Electrical, Electronic, and Information Engineering, Graduate School of Engineering, Osaka University, 2-1 Yamada-oka, Suita, Osaka 565-0871, Japan.

Objective: Microstimulation to the cortical tissue applied with penetrating electrodes delivers current that spreads concentrically around the electrode tip and is known to evoke focal visual sensations, i.e. phosphenes. However, to date, there is no direct evidence depicting the spatiotemporal properties of neuronal activity induced immediately after microstimulation and how such activity drives the subsequent local cortical circuits.

Approach: In the present study, we imaged the spatiotemporal distribution of action potentials (APs) directly induced by microstimulation and the subsequent trans-synaptic signal propagation using a voltage-sensitive dye (VSD) and a calcium-sensitive dye (CaSD) in slice preparations of the mouse primary visual cortex.

Main Results: The directly induced APs were confined to the close vicinity of the electrode tip, and the effective distance of excitation was proportional to the square root of the current intensity. The excitation around the electrode tip in layer IV mainly propagated to layer II/III to further induce the subsequent focal activation in downstream local cortical circuits. The extent of activation in the downstream circuits was restrained by competitive interactions between excitatory and inhibitory signals. Namely, the spread of the excitation to lateral neighbor neurons along the layer II/III was confined by the delayed inhibition that also spread laterally at a faster rate.

Significance: These observations indicate that dynamic interactions between excitatory and inhibitory signals play a critical role in the focal activation of a cortical circuit in response to intracortical microstimulation and, therefore, in evoking a localized phosphene.
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http://dx.doi.org/10.1088/1741-2552/ab0b80DOI Listing
June 2019

Validation of the prediction rules identifying drug-resistant pathogens in community-onset pneumonia.

Infect Drug Resist 2018 11;11:1703-1713. Epub 2018 Oct 11.

Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan,

Background: Appropriate initial antibiotic treatment and avoiding administration of unnecessary broad-spectrum antibiotics are important for the treatment of pneumonia. To achieve this, assessment of risk for drug-resistant pathogens (DRPs) at diagnosis is essential.

Purpose: The aim of this study was to validate a predictive rule for DRPs that we previously proposed (the community-acquired pneumonia drug-resistant pathogen [CAP-DRP] rule), comparing several other predictive methods.

Patients And Methods: A prospective observational study was conducted in hospitalized patients with community-onset pneumonia at four institutions in Japan. Pathogens identified as not susceptible to ceftriaxone, ampicillin-sulbactam, macrolides, and respiratory fluoroquinolones were defined as CAP-DRPs.

Results: CAP-DRPs were identified in 73 (10.1%) of 721 patients analyzed. The CAP-DRP rule differentiated low vs high risk of CAP-DRP at the threshold of ≥3 points or 2 points plus any of methicillin-resistant specific factors with a sensitivity of 0.45, specificity of 0.87, positive predictive value of 0.47, negative predictive value of 0.87, and accuracy of 0.79. Its discrimination performance, area under the receiver operating characteristic curve, was 0.73 (95% confidence interval 0.66-0.79). Specificity of the CAP-DRP rule against CAP-DRPs was the highest among the six predictive rules tested.

Conclusion: The performance of the predictive rules and criteria for CAP-DRPs was limited. However, the CAP-DRP rule yielded high specificity and could specify patients who should be treated with non-broad-spectrum antibiotics, eg, a non-pseudomonal β-lactam plus a macrolide, more precisely.
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http://dx.doi.org/10.2147/IDR.S165669DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6188199PMC
October 2018

Fungal endocarditis after transcatheter aortic valve replacement (TAVR): Case report and review of literature.

J Infect Chemother 2019 Mar 20;25(3):215-217. Epub 2018 Sep 20.

Department of Infectious Diseases, Nagoya University Hospital, Japan.

The reported number of transcatheter aortic valve replacement-associated infective endocarditis (TAVR-IE) cases has been increasing worldwide, but information about the incidence and clinical features of fungal TAVR-IE is quite limited. We present a patient who acquired TAVR-IE caused by Candida parapsilosis four month after TAVR, who was successfully treated redo-aortic valve replacement and prolonged antifungal therapy.
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http://dx.doi.org/10.1016/j.jiac.2018.08.017DOI Listing
March 2019

Active surveillance in response to the identification of a single carbapenemase-producing Escherichia coli at a Japanese university hospital.

J Infect Chemother 2018 Dec 23;24(12):1013-1015. Epub 2018 Jun 23.

Department of Infectious Diseases, Nagoya University Hospital, Aichi, Japan. Electronic address:

This report described the experience of active surveillance culture implemented in response to the identification of a single carbapenemase-producing Escherichia coli in a Japanese university hospital. It revealed a horizontal transmission event and an additional asymptomatic carrier of carbapenemase-producing Escherichia coli with unique drug susceptibility and resistance gene profiles. Early implementation of active surveillance culture as a part of multifaceted infection control measures appeared to be useful to control further transmission of carbapenemase-producing Escherichia coli even in the low endemic facility. Further investigations on the timing and usefulness of active surveillance culture in the control of carbapenemase-producing Enterobacteriaceae would be warranted.
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http://dx.doi.org/10.1016/j.jiac.2018.05.013DOI Listing
December 2018

Comprehensive detection of pathogens in immunocompromised children with bloodstream infections by next-generation sequencing.

Sci Rep 2018 02 28;8(1):3784. Epub 2018 Feb 28.

Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Bloodstream infection (BSI) is a severe complication in immunocompromised patients. Next-generation sequencing (NGS) allows us to analyze comprehensively and quantitatively all microorganisms present in a clinical sample. Thirty-five pediatric patients (12 with BSI and 23 with suspected BSI/negative blood culture) were enrolled. Plasma/serum samples were used for sequencing and the results were compared with those from blood culture. Sequencing reads of bacteria isolated in blood culture were identified by NGS in all plasma/serum samples at disease onset. Bacteria isolated in blood culture were identical to the dominant bacteria by NGS in 8 of 12 patients. Bacterial reads per million reads of the sequence depth (BR) > 200 and relative importance values of the dominant bacteria (P1) > 0.5 were employed to determine causative pathogens. Causative pathogens were detected using these criteria in 7 of 12 patients with BSI. Additionally, causative bacteria were detected in the plasma/serum at 7 days before disease onset in two patients with catheter-related BSI. Causative pathogens, including virus, were identified in three patients with suspected BSI. Lastly, a total of 62 resistance genes were detected by NGS. In conclusion, NGS is a new method to identify causative microorganisms in BSI and may predict BSI in some patients.
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http://dx.doi.org/10.1038/s41598-018-22133-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5830625PMC
February 2018

Evaluation of treatment outcomes of patients with MRSA bacteremia following antimicrobial stewardship programs with pharmacist intervention.

Int J Clin Pract 2018 Mar 8;72(3):e13065. Epub 2018 Feb 8.

Laboratory of Pharmacy Practice and Social Science, Gifu Pharmaceutical University, Gifu, Japan.

Background: Methicillin-resistant Staphylococcus aureus bacteremia (MRSA-B) is associated with high mortality and implementing an appropriate antimicrobial stewardship (AS) program with treatment intervention is essential. The aim of this study was to evaluate the impact of AS with pharmacist intervention on patients with MRSA-B.

Methods: Patients who were diagnosed with MRSA-B between January 2012 and April 2013 were defined as the pre-intervention group, while those diagnosed between May 2013 and December 2015 were defined as the intervention group (ie, AS with pharmacist intervention). The factors affecting bundle compliance rates and mortality were analysed.

Result: The pre-intervention group comprised 43 patients and the intervention group comprised 51 patients. Bundle compliance rates were estimated as follows in the intervention group: an increase was observed in the appropriate duration of therapy (from 44.8% to 72.1%, P = .027), incidences of the early use of anti-MRSA drugs (from 62.3% to 82.4%, P = .038), and the number of negative follow-up blood cultures (from 40.0% to 80.0%, P < .001), and a decrease was observed for 30-day mortality (from 41.8% to 21.6%, P = .044) and hospital mortality (from 58.1% to 27.5%, P = .003). In multivariate analysis, the intervention group was independent of 30-day mortality and hospital mortality risk reduction factors (odds ratio [OR], 0.33; 95% confidence interval [CI], 0.12-0.86, and OR, 0.20; 95% CI, 0.07-0.53).

Conclusions: AS programs with pharmacist intervention improve mortality in patients with MRSA-B.
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http://dx.doi.org/10.1111/ijcp.13065DOI Listing
March 2018

Preoperative biliary colonization/infection caused by multidrug-resistant (MDR) pathogens in patients undergoing major hepatectomy with extrahepatic bile duct resection.

Surgery 2018 05 15;163(5):1106-1113. Epub 2018 Feb 15.

Division of Surgical Oncology, Department of Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan. Electronic address:

Background: The aim of this study was to review the surgical outcomes of patients who underwent major hepatectomy with extrahepatic bile duct resection after preoperative biliary drainage with a particular focus on the impact of preoperative biliary colonization/infection caused by multidrug-resistant pathogens.

Methods: Medical records of patients who underwent hepatobiliary resection after preoperative external biliary drainage between 2001 and 2015 were reviewed retrospectively. Prophylactic antibiotics were selected according to the results of drug susceptibility tests of surveillance bile cultures.

Results: In total, 565 patients underwent surgical resection. Based on the results of bile cultures, the patients were classified into three groups: group A, patients with negative bile cultures (n = 113); group B, patients with positive bile cultures without multidrug-resistant pathogen growth (n = 416); and group C, patients with multidrug-resistant pathogen-positive bile culture (n = 36). The incidence of organ/space surgical site infection, bacteremia, median duration of postoperative hospital stay, and the mortality rate did not differ among the three groups. The incidence of incisional surgical site infection and infectious complications caused by multidrug-resistant pathogens was significantly higher in group C than in groups A and B. Fifty-two patients had postoperative infectious complications caused by multidrug-resistant pathogens. Multivariate analysis identified preoperative multidrug-resistant pathogen-positive bile culture as a significant independent risk factor for postoperative infectious complications caused by multidrug-resistant pathogens (P< .001).

Conclusion: Major hepatectomy with extrahepatic bile duct resection after biliary drainage can be performed with acceptable rates of morbidity and mortality using appropriate antibiotic prophylaxis, even in patients with biliary colonization/infection caused by multidrug-resistant pathogens.
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http://dx.doi.org/10.1016/j.surg.2017.12.031DOI Listing
May 2018

The first report of Japanese antimicrobial use measured by national database based on health insurance claims data (2011-2013): comparison with sales data, and trend analysis stratified by antimicrobial category and age group.

Infection 2018 Apr 22;46(2):207-214. Epub 2017 Dec 22.

Department of infectious Diseases, Nagoya University Hospital, Nagoya, Aichi, Japan.

Purpose: Our objective was to evaluate the utility of the national database (NDB) based on health insurance claims data for antimicrobial use (AMU) surveillance in medical institutions in Japan.

Methods: The population-weighted total AMU expressed as defined daily doses (DDDs) per 1000 inhabitants per day (DID) was measured by the NDB. The data were compared with our previous study measured by the sales data. Trend analysis of DID from 2011 to 2013 and subgroup analysis stratified by antimicrobial category and age group were performed.

Results: There was a significant linear correlation between the AMUs measured by the sales data and the NDB. Total oral and parenteral AMUs (expressed in DID) were 1.04-fold from 12.654 in 2011 to 13.202 in 2013 and 1.13-fold from 0.734 to 0.829, respectively. Percentage of oral form among total AMU was high with more than 94% during the study period. AMU in the children group (0-14 years) decreased from 2011 to 2013 regardless of dosage form, although the working age group (15-64 years) and elderly group (65 and above years) increased. Oral AMU in the working age group was approximately two-thirds of those in the other age groups. In contrast, parenteral AMU in the elderly group was extremely high compared to the other age groups.

Conclusions: The trend of AMU stratified by antimicrobial category and age group were successfully measured using the NDB, which can be a tool to monitor outcome indices for the national action plan on antimicrobial resistance.
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http://dx.doi.org/10.1007/s15010-017-1097-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5871632PMC
April 2018

Mortality in patients with community-onset pneumonia at low risk of drug-resistant pathogens: Impact of β-lactam plus macrolide combination therapy.

Respirology 2018 05 14;23(5):526-534. Epub 2017 Dec 14.

Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Background And Objective: Drug-resistant pathogen (DRP) risk stratification is important for choosing a treatment strategy for community-onset pneumonia. Evidence for benefits of non-antipseudomonal β-lactam plus macrolide combination therapy (BLM) on mortality is limited in patients at low DRP risk. Risk factors for mortality remain to be clarified.

Methods: Post hoc analysis using a prospective multicentre study cohort of community-onset pneumonia was performed to assess 30-day differences in mortality between non-antipseudomonal β-lactam monotherapy (BL) and BLM groups. Logistic regression analysis was performed to assess the therapeutic effect and risk factors for mortality in patients at low DRP risk.

Results: In total, 594 patients with community-onset pneumonia at low DRP risk (369 BL and 225 BLM) were analysed. The 30-day mortality in BL and BLM was 13.8% and 1.8%, respectively (P < 0.001). Multivariate analysis showed that BLM reduced the 30-day mortality (adjusted odds ratio: 0.28, 95% CI: 0.09-0.87) compared with BL. Independent prognostic factors for 30-day mortality included arterial partial pressure of carbon dioxide (PaCO ) > 50 mm Hg, white blood cell count < 4000/mm , non-ambulatory status, albumin < 3.0 g/dL, haematocrit < 30%, age ≥ 80 years, respiratory rate > 25/min and body temperature < 36°C.

Conclusion: In patients with community-onset pneumonia at low DRP risk, BLM treatment reduced 30-day mortality compared with BL. Independent risk factors for mortality are potential confounding factors when assessing antibiotic effects in randomized clinical trials.
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http://dx.doi.org/10.1111/resp.13232DOI Listing
May 2018

Age-related changes in the spatiotemporal responses to electrical stimulation in the visual cortex of rats with progressive vision loss.

Sci Rep 2017 10 26;7(1):14165. Epub 2017 Oct 26.

Biosystems and Devices Area, Division of Electrical, Electronic and Information Engineering, Department of Electronic Engineering, Graduate School of Engineering, Osaka University, 2-1 Yamadaoka, Suita, Osaka, 565-0871, Japan.

The Royal College of Surgeons (RCS) rat gradually loses vision due to retinal degeneration. Previous physiological studies have depicted the progressive loss of optical responses in the visual pathway, including the primary visual cortex (V1), over the course of retinal degeneration in the RCS rat. However, little is known about how the excitability of the V1 circuit changes during over the course of the gradual loss of visual signal input from the retina. We elucidated the properties of responses to electrical stimulations directly applied to V1 at different stages of vision input loss in the RCS rat in reference to those of the Long-Evans (LE) rat, using in vivo voltage-sensitive dye imaging. The V1 neuronal network of the RCS rat exhibited an excitatory response comparable to the LE rat. The excitatory response was maintained even long after total loss of the visual signal input from the retina. However, the response time-course suggested that the suppressive response was somewhat debilitated in the RCS rat. This is the first experiment demonstrating the long-term effect of retinal degeneration on cortical activities. Our findings provide the physiological fundamentals to enhance the preclinical research of cortical prostheses with the use of the RCS rat.
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http://dx.doi.org/10.1038/s41598-017-14303-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5658441PMC
October 2017

Imaging of population spikes induced by repetitive stimulus pulses in mouse cerebral slices in vitro.

Annu Int Conf IEEE Eng Med Biol Soc 2017 Jul;2017:1109

Effects of the repetitive current pulses of microstimulation on spatio-temporal neuronal excitations in the primary visual cortex in mouse cerebral slices in vitro were examined by utilizing the voltage-sensitive dye imaging technique. The amplitude and spatial extent of the population spike directly induced by the stimulus pulse was significantly reduced in response to successive stimulus pulses at 200 Hz. This suggested that the high-frequency microstimulation may not be efficient for inducing the neuronal spiking, at least, in vitro.
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http://dx.doi.org/10.1109/EMBC.2017.8037022DOI Listing
July 2017

Risk factors for and role of OprD protein in increasing minimal inhibitory concentrations of carbapenems in clinical isolates of Pseudomonas aeruginosa.

J Med Microbiol 2017 Nov 6;66(11):1562-1572. Epub 2017 Oct 6.

Department of Infectious Diseases, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.

Purpose: This study examined the risk factors for, and molecular mechanisms underlying, the increase in carbapenem minimum inhibitory concentrations (MICs) in clinical isolates of Pseudomonas aeruginosa.

Methodology: Consecutive clinical isolates of P. aeruginosa were collected. The MicroScan WalkAway system detected more than fourfold increases in the MICs of carbapenems in P. aeruginosa isolates serially recovered from some patients during their clinical course. The clinical risk factors associated with this increase were examined by multiple logistic regression analysis. Western blot analysis and nucleotide sequencing of the oprD gene of 19 clonally related and paired P. aeruginosa isolates from the same patients were undertaken to examine the mechanisms underlying the increase in MICs.

Results: The results showed that prior use of carbapenems (OR, 2.799; 95 % CI, 1.088-7.200; P=0.033) and the use of ventilators or tracheostomies (OR, 2.648; 95 % CI, 1.051-6.671; P=0.039) were risk factors for increased carbapenem MICs. Analysis of the underlying mechanisms revealed that loss of functional OprD protein due to mutation of the oprD gene tended to occur in P. aeruginosa isolates with imipenem MICs of more than 8 µg ml; a reduction in OprD expression was observed in P. aeruginosa isolates with imipenem MICs of 4 or 8 µg ml. This difference in the resistance mechanism was not correlated with the MICs of meropenem.

Conclusion: This difference in the resistance mechanism of P. aeruginosa indicates a critical breakpoint at an imipenem MIC of 8 µg ml, in accordance with EUCAST criteria. Reducing carbapenem use will prevent P. aeruginosa clinical isolates from developing resistance to carbapenems.
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http://dx.doi.org/10.1099/jmm.0.000601DOI Listing
November 2017

Recurrent bacteremia and liver abscess caused by Clostridium difficile: A case report.

Medicine (Baltimore) 2017 Sep;96(35):e7969

Department of Infectious Diseases, Nagoya University Hospital Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Aichi Department of Clinical Infectious Diseases Department of Infection Control and Prevention, Aichi Medical University Hospital, Nagakute, Aichi, Japan.

Rationale: Clostridium difficile bacteremia (CDB) and liver abscess is a quite rare presentation of C. difficile infection.

Patients Concerns: A 74-year-old male with primary biliary cirrhosis and hepatocellular carcinoma who underwent transarterial chemoembolization (TACE) developed a high fever on post-TACE day 14. Intravenous ceftriaxone and following meropenem were administered, however, his clinical response was poor. On post-TACE day 24, 2 sets of blood culture were taken due to elevation of C-reactive protein levels.

Diagnosis: CDB, caused by bacterial translocation.

Interventions: Intravenous vancomycin and oral metronidazole were administered for two weeks.

Outcomes: One month after recurrent CDB, the patient was re-admitted due to a liver abscess at the same site of TACE. C. difficile was isolated from the liver abscess and the patient received 6 weeks of oral metronidazole treatment. CDB and liver abscess have not recurred since completion of antibiotic treatment.

Lessons: The spore-forming ability of C. difficile may contributed to the recurrent CDB episodes and liver abscess formation in necrotic liver tissue following TACE, and long-term metronidazole therapy was considered to be effective to C. difficile liver abscess.
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http://dx.doi.org/10.1097/MD.0000000000007969DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5585525PMC
September 2017

Stoichiometric analysis of oligomeric states of three class-A GPCRs, chemokine-CXCR4, dopamine-D2, and prostaglandin-EP1 receptors, on living cells.

J Pept Sci 2017 Jul 18;23(7-8):650-658. Epub 2017 Jun 18.

Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida-Shimoadachicho, Sakyo-ku, Kyoto, 606-8501, Japan.

G-protein-coupled receptors (GPCRs) form the largest family of transmembrane receptors, and their oligomerization has been suggested to be related to their functions. Despite extensive studies, their oligomeric states are highly controversial. One of the reasons is the overestimation of oligomerization by conventional methods. We recently established a stoichiometric analysis method for precisely determining the oligomeric state of membrane proteins on living cells with the combined use of the coiled-coil labeling method and a spectral imaging technique and showed that the prototypical class-A GPCR β -adrenergic receptor (β AR) did not form functional oligomers. In this study, we expanded our study to three well-studied class-A GPCRs: C-X-C chemokine receptor of stromal cell-derived factor-1α (CXCR4), dopamine receptor D2 short isotype (D2R), and prostaglandin E receptor subtype 1 (EP1R). We found that these receptors did not form constitutive homooligomers. The receptors exhibited calcium signaling upon agonist stimulation as monomers, although CXCR4 and EP1R gradually clustered after fast signaling. We conclude that homooligomerization is not necessary for the signal transductions of these four class-A GPCRs. Copyright © 2017 European Peptide Society and John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/psc.3020DOI Listing
July 2017

Retinal Circuit Emulator With Spatiotemporal Spike Outputs at Millisecond Resolution in Response to Visual Events.

IEEE Trans Biomed Circuits Syst 2017 06 19;11(3):597-611. Epub 2017 May 19.

Graduate School of Engineering, Osaka University, Suita, Japan.

To gain insights on how visual information of the real world is filtered, compressed, and encoded by the vertebrate retinas, emulating in silico the spatiotemporal patterns of the graded and action potentials of neuronal responses to natural visual scenes on biological time scale is a feasible approach. As a basic platform for such an emulation, we here developed a compact hardware system comprising an analog silicon retina and a field-programmable gate array module. With utilizing the Izhikevich formalism, a retinal circuit model that emulates spiking of ganglion cells was implemented in this system. The emulated spike timing had the resolution of about 2 ms relative to the stimulus onset and was little affected by timings of the synchronous frame sampling in the silicon retina. Thus, the emulator can mimic the event-driven spike outputs of biological retinas. The system was useful for simultaneously visualizing neural images of both the graded potentials and the spikes in response to real live visual scenes. Since our emulator system is reconfigurable, it provides a flexible platform for investigating visual functions of retinal circuits under natural visual environment.
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http://dx.doi.org/10.1109/TBCAS.2017.2662659DOI Listing
June 2017

Collaboration with an infection control team for patients with infection after spine surgery.

Am J Infect Control 2017 Jul 22;45(7):767-770. Epub 2017 Feb 22.

Department of Orthopedic Surgery, Nagoya University Graduate School of Medicine, Aichi, Japan.

Background: The risk of infection, including surgical site infection (SSI), after spine surgery has increased due to aging and more immunocompromised hosts. An infection control team (ICT) is responsible for management of health care-associated infections at our institution.

Methods: The study subjects were 40 patients (18 men and 22 women with an average age of 54 years) referred to the ICT after spine surgery since 2010. Pathogenic bacteria and treatment in these cases were reviewed.

Results: Collaboration with the ICT involved guidance on use of antibiotics for infection in 30 patients (16 SSI and 14 non-SSI) and a search for the infection focus for fever of unknown origin in 10 patients (7 patients were found to have urinary tract infections and 2 patients were found to have pneumonia). The detection rate of causative bacteria in ICT consultation was 88% (35 out of 40 patients). SSI patients with instrumentation involved had a significantly higher rate of methicillin-resistant Staphylococcus aureus infection compared with those without instrumentation (42% vs 13%; P < .05).

Discussion: All cases of SSI with instrumentation involved were cured by ICT support without removal of instrumentation. Early assistance from the ICT was important for prevention of worsening of methicillin-resistant S aureus infection.

Conclusions: Collaboration with the ICT was helpful for detection of pathogenic bacteria and allowed appropriate use of antibiotics at an early stage.
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http://dx.doi.org/10.1016/j.ajic.2017.01.013DOI Listing
July 2017

Pneumococcal biliary tract infections - How rare are they?

J Infect Chemother 2017 Jun 24;23(6):415-418. Epub 2016 Dec 24.

Department of Infectious Diseases, Nagoya University Hospital, Japan; Department of Infectious Diseases, Nagoya University Graduate School of Medicine, Japan. Electronic address:

Pneumococcal biliary tract infections (PBTIs) were reported as rare due to the bacterium's bile solubility. The purpose of this study was to determine the occurrence and clinical characteristics of PBTIs. A retrospective case series review was conducted from January 2006 to August 2014 at a tertiary referral university hospital in Japan. Patients with a blood or bile culture positive for Streptococcus pneumoniae diagnosed with definite cholangitis or cholecystitis according to Tokyo Guideline 2013 were enrolled in this study. Data on clinical information, treatments, and outcomes were collected. During 104 months, 48 cases of positive blood cultures and 13 cases of positive bile cultures were recorded, and after excluding 43 and 5 of these, respectively, a total of 10 patients were diagnosed with PBTI. Most patients (9/10) had biliary tract problems and biliary devices in place. PBTIs were not rare; conversely, they were a relatively common cause of pneumococcal bacteremia in this center treating a high volume of biliary tract illnesses.
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http://dx.doi.org/10.1016/j.jiac.2016.11.008DOI Listing
June 2017

Japanese antimicrobial consumption surveillance: First report on oral and parenteral antimicrobial consumption in Japan (2009-2013).

J Glob Antimicrob Resist 2016 12 6;7:19-23. Epub 2016 Aug 6.

Department of Pharmacy, Mie University Hospital, Tsu, Mie, Japan. Electronic address:

No reliable national antimicrobial consumption data have been available in Japan. The Japanese antimicrobial consumption surveillance (JACS) project started to collect data nationwide on antimicrobial consumption. This paper provides the first sales data from the JACS project on oral and parenteral antimicrobial consumption in Japan as well as the trends for the years from 2009 to 2013. The population-weighted total consumption was expressed as defined daily doses (DDDs) per 1000 inhabitants per day (DID). The value of DID increased from 14.7 in 2009 to 15.8 in 2013. Notably, oral antimicrobials accounted for 92.6% (mean of 2009, 2011 and 2013) of total consumption. Oral third-generation cephalosporins, macrolides and fluoroquinolones accounted for 77.1% (mean of 2009, 2011 and 2013) of oral consumption. Consumption of antimicrobials has increased during the years 2009 and 2013 regardless of the dosage form. This is the first report regarding the population-weighted consumption of oral and parenteral antimicrobials in Japan during the years 2009 and 2013. These results provide useful information for combating the menace of antimicrobial resistance in Japan.
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http://dx.doi.org/10.1016/j.jgar.2016.07.002DOI Listing
December 2016
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