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The global emergence of -COVID-19 has prompted rapid therapeutic and vaccine advancements; however, clinical evidence remains limited. With around a 50% fatality rate for COVID-19 patients with acute respiratory distress syndrome (ARDS), early intervention is crucial. This report details a severe case of post-COVID-19 thrombocytopenia in a 79-year-old man and emphasizes its critical nature. Despite negative initial COVID-19 test results, subsequent positive results led to treatment initiation, and severe thrombocytopenia persisted resulting in bleeding complications and death. Recognized as a hematological manifestation of COVID-19, thrombocytopenia in this geriatric patient highlights the need for extended post-COVID-19 monitoring and management. This underscores the importance of vigilance and timely intervention, especially in vulnerable populations, and emphasizes the need for further research to understand the intricate relationship between COVID-19 and thrombocytopenia.

Background: MRSA (methicillin-resistant Staphylococcus aureus)-infective endocarditis (IE) is associated with high morbidity and mortality. This study aimed to assess data from patients with MRSA-IE across multiple facilities in Japan, with a specific focus on antimicrobial therapy and prognosis., Methods: This retrospective study enrolled patients with a confirmed diagnosis of IE attributed to MRSA, spanning the period from January 2015 to April 2019., Results: Sixty-four patients from 19 centers were included, with a median age of 67 years. The overall mortality rate was 28.1% at 30 days, with an in-hospital mortality of 45.3%. The most frequently chosen initial anti-MRSA agents were glycopeptide in 67.2% of cases. Daptomycin and linezolid were selected as initial therapy in 23.4% and 17.2% of cases, respectively. Approximately 40% of all patients underwent medication changes due to difficulty in controlling infection or drug-related side effects. Significant prognostic factors by multivariable analysis were DIC for 30-day mortality and surgical treatment for 30-day and in-hospital mortality. For vancomycin as initial monotherapy, there was a trend toward a worse prognosis for 30-day and in-hospital mortality (OR, 6.29; 95%CI, 1.00-39.65; p = 0.050, OR, 3.61; 95%CI, 0.93-14.00; p = 0.064). Regarding the choice of initial antibiotic therapy, statistical analysis did not show significant differences in prognosis., Conclusion: Glycopeptide and daptomycin were the preferred antibiotics for the initial therapy of MRSA-IE. Antimicrobial regimens were changed for various reasons. Prognosis was not significantly affected by choice of antibiotic therapy (glycopeptide, daptomycin, linezolid), but further studies are needed to determine which antimicrobials are optimal as first-line agents., Competing Interests: Declaration of Competing interest Tokimatsu I. received scholarship donations from Shionogi Pharmaceuticals, Inc. and Daiichi Sankyo Co. Ltd. Ukimura A. received scholarship donations from Shionogi Pharmaceuticals, Inc. Hiroshige Mikamo received speaker honoraria from MSD K.K., FUJIFILM Toyama Chemical Co., Ltd., Miyarisan Pharmaceutical Co., Daiichi Sankyo Co., Ltd., Pfizer Japan Inc., Sanofi K.K., Sumitomo Pharma Co., Ltd., Kyorin Pharmaceutical Co., Ltd., Shionogi & Co., Ltd. Japan, Kowa Co. Ltd., Gilead Sciences K.K., GSK Group of Companies, Saraya Co. Ltd., Tsumura & Co. Japan, Nippon Becton Dickinson Company, Ltd., and FUKOKU Co., Ltd., grant supports from Asai Kasei Pharma Co., Shionogi & Co., Ltd., Sumitomo Pharma Co., Ltd., and FUKOKU Co., Ltd. Mitsutake K, Shinya N, Seki M, Ohara T, Uemura K, Fukunaga M, Sakai J, Nagao M, Sata M, Hamada Y, Kawasuji H, Yamamoto Y, Nakamatsu M, Koizumi Y, Aoyagi T, Sawai T, Tanaka T, Izumikawa K, Takayama Y, Nakamura K, Kanemitsu K, Nakajima K, and Akine D have no conflict of interest., (Copyright © 2024 Japanese Society of Chemotherapy, Japanese Association for Infectious Diseases, and Japanese Society for Infection Prevention and Control. Published by Elsevier Ltd. All rights reserved.)

Background: Infective endocarditis (IE) caused by MRSA (methicillin-resistant Staphylococcus aureus) is associated with a high mortality rate. This study aimed to elucidate the characteristics of patients with MRSA-IE in Japan and identify the factors associated with prognosis., Methods: This retrospective study included patients with a confirmed diagnosis of IE caused by MRSA, between January 2015 and April 2019., Results: A total of 65 patients from 19 centers were included, with a mean age of 67 years and 26 % were female. Fifty percent of the patients with IE were had nosocomial infections and 25 % had prosthetic valve involvement. The most common comorbidities were hemodialysis (20 %) and diabetes (20 %). Congestive heart failure was present in 86 % of patients (NYHA class I, II: 48 %; III, IV: 38 %). The 30-day and in-hospital mortality rates were 29 % and 46 %, respectively. Multi-organ failure was the primary cause of death, accounting for 43 % of all causes of death. Prognostic factors for in-hospital mortality were age, disseminated intravascular coagulation, daptomycin and/or linezolid as initial antibiotic therapy, and surgery. Surgical treatment was associated with a lower mortality rate (odds ratio [OR], 0.026; 95 % confidence interval [CI], 0.002-0.382; p = 0.008 for 30-day mortality and OR, 0.130; 95 % CI; 0.029-0.584; p = 0.008 for in-hospital mortality)., Conclusion: Mortality due to MRSA-IE remains high. Surgical treatment is a significant prognostic predictor of MRSA-IE., Competing Interests: Declaration of competing interest Tokimatsu I. received scholarship donations from Shionogi Pharmaceuticals, Inc. and Daiichi Sankyo Co., Ltd. Ukimura A. received scholarship donations from Shionogi Pharmaceuticals Inc. Hiroshige Mikamo received speaker honoraria from MSD K.K., FUJIFILM Toyama Chemical Co., Ltd., Miyarisan Pharmaceutical Co., Daiichi Sankyo Co., Ltd., Pfizer Japan Inc., Sanofi K.K., Sumitomo Pharma Co., Ltd., Kyorin Pharmaceutical Co., Ltd., Shionogi & Co., Japan. Ltd., Kowa Co. Ltd., Gilead Sciences K.K., the GSK Group of Companies, Saraya Co. Ltd., and Tsumura and Co. Japan, Nippon Becton Dickinson Company, Ltd., and FUKOKU Co., Ltd., and grant support from Asai Kasei Pharma Co., Shionogi & Co., Ltd., Sumitomo Pharma Co., Ltd., and FUKOKU Co., Ltd. Mitsutake K, Shinya N, Seki M, Ohara T, Uemura K, Fukunaga M, Sakai J, Nagao M, Sata M, Hamada Y, Kawasuji H, Yamamoto Y, Nakamatsu M, Koizumi Y, Aoyagi T, Sawai T, Tanaka T, Izumikawa K, Takayama Y, Nakamura K, Kanemitsu K, Nakajima K, and Akine D have no conflict of interest., (Copyright © 2024 Japanese Society of Chemotherapy, Japanese Association for Infectious Diseases, and Japanese Society for Infection Prevention and Control. Published by Elsevier Ltd. All rights reserved.)

The trends and prevalence of antimicrobial susceptibility of pathogens vary by country, region, and time. Long-term regular surveillance is required to investigate trends in the antimicrobial resistance of various isolated bacterial pathogens. We report the results of a nationwide surveillance on the antimicrobial susceptibility of bacterial respiratory pathogens in Japan conducted by the Japanese Society of Chemotherapy, the Japanese Association for Infectious Diseases, and the Japanese Society for Clinical Microbiology. The isolates were collected from clinical specimens obtained from adult patients who visited a collaborating medical facility between June 2019 and December 2020 and were diagnosed with respiratory tract infections by a physician. Antimicrobial susceptibility testing was performed in a centralized laboratory according to the methods recommended by the Clinical and Laboratory Standards Institute. Susceptibility testing was performed for 932 strains (201 Staphylococcus aureus, 158 Streptococcus pneumoniae, 6 S. pyogenes, 136 Haemophilus influenzae, 127 Moraxella catarrhalis, 141 Klebsiella pneumoniae, and 163 Pseudomonas aeruginosa) collected from 32 facilities in Japan. The proportions of methicillin-resistant S. aureus and penicillin-resistant S. pneumoniae were 35.3% and 0%, respectively. In H. influenzae, 16.2% and 16.9% were β-lactamase-producing ampicillin resistant and β-lactamase-negative ampicillin resistant, respectively. Extended-spectrum β-lactamase-producing K. pneumoniae accounted for 5.0% of all K. pneumoniae infections. Carbapenemase-producing K. pneumoniae and multi-drug-resistant P. aeruginosa with metallo-β-lactamase were not detected in this study. This surveillance will be a useful reference for treating respiratory infections in Japan and will provide evidence to enhance the appropriate use of antimicrobial agents., Competing Interests: Declaration of competing interest Issei Tokimatsu received research funding from Asahi Kasei Pharma Corporation, and scholarship donations from Shionogi & Co., Ltd., and Daiichi Sankyo Co., Ltd. Tetsuya Matsumoto received speaker honoraria from MSD K.K., and Pfizer Japan Inc. Makoto Miki hold shares in Daiichi Sankyo Co., Ltd., and received speaker honoraria from Kyorin Pharmaceutical Co., Ltd. Tomotaro Wakamura is an employee of Sumitomo Pharma Co., Ltd. Daisuke Kurai received research funding from Daiichi Sankyo Co., Ltd., and scholarship donations from Shionogi & Co., Ltd. Hiroki Tsukada received speaker honoraria from Kyorin Pharmaceutical Co., Ltd. Nobuki Aoki received speaker honoraria from Kyorin Pharmaceutical Co., Ltd. Hiroshige Mikamo received speaker honoraria from Nippon Becton Dickinson Company, Ltd., Astellas Pharma Inc., Sumitomo Pharma Co., Ltd. (formerly Sumitomo Dainippon Pharma Co., Ltd.), Pfizer Japan Inc., MSD K.K., Daiichi Sankyo Co., Ltd., Fujifilm Toyama Chemical Co., Ltd., Miyarisan Pharmaceutical Co. Ltd., Kyorin Pharmaceutical Co., Ltd., Gilead Sciences K.K., Saraya Co., Ltd., Tsumura & Co., Meiji Seika Pharma Co., Ltd., Sanofi K.K., Shionogi & Co., Ltd., Fukoku Co., Ltd., GlaxoSmithKline K.K., Kowa Company, Ltd., research funding from Fukoku Co., Ltd., Sekisui Medical Co., Ltd., Meiji Seika Pharma Co., Ltd., Pfizer Japan Inc., Saraya Co., Ltd., Miyarisan Pharmaceutical Co. Ltd., Roche Diagnostics K.K., ASKA Pharmaceutical Co., Ltd., Tosoh Corporation, Bruker Japan K.K., Abbott Diagnostics Medical Co., Ltd., Ortho Clinical Diagnostics K.K., Kyorin Pharmaceutical Co., Ltd., and scholarship donations from Asahi Kasei Pharma Co., Shionogi & Co., Ltd., Daiichi Sankyo Co., Ltd., Fujifilm Toyama Chemical Co., Ltd., Sumitomo Pharma Co., Ltd. (formerly Sumitomo Dainippon Pharma Co., Ltd.), Fukoku Co., Ltd., and Morii Co., Ltd. Atsushi Nakamura received speaker honoraria from Kyorin Pharmaceutical Co., Ltd., MSD K.K., Astellas Pharma Inc. Akira Ukimura received scholarship donations from Shionogi & Co., Ltd. Hiroshi Kakeya received speaker honoraria from MSD K.K., Sumitomo Pharma Co., Ltd. (formerly Sumitomo Dainippon Pharma Co., Ltd.), Shionogi & Co., Ltd., Asahi Kasei Pharma Corporation., Astellas Pharma Inc., and Pfizer Japan Inc. Katsunori Yanagihara received speaker honoraria from Daiichi Sankyo Co., Ltd., MSD K.K., Astellas Pharma Inc., and Taisho Pharma Co., Ltd. (formerly Taisho Toyama Pharmaceutical Co., Ltd.), research funding from Fujifilm Toyama Chemical Co., Ltd., Meiji Seika Pharma Co., Ltd., Kyorin Pharmaceutical Co., Ltd., and Shionogi & Co., Ltd., and scholarship donations from Sumitomo Pharma Co., Ltd. (formerly Sumitomo Dainippon Pharma Co., Ltd.), Fujifilm Toyama Chemical Co., Ltd., Taiho Pharmaceutical Co., Ltd., and Kyorin Pharmaceutical Co., Ltd., (Copyright © 2023 Japanese Society of Chemotherapy, Japanese Association for Infectious Diseases, and Japanese Society for Infection Prevention and Control. Published by Elsevier Ltd. All rights reserved.)

The antibiotic spectrum is not reflected in conventional antimicrobial metrics. Days of antibiotic spectrum coverage (DASC) is a novel quantitative metric for antimicrobial consumption developed with consideration of the antibiotic spectrum. However, there were no data regarding disease and pathogen-specific DASC. Thus, this study aimed to evaluate the DASC trend in patients with bloodstream infections (BSIs). DASC and days of therapy (DOT) of in-patients with positive blood culture results during a 2-year interval were evaluated. Data were aggregated to calculate the DASC, DOT, and DASC/DOT per patient stratified by pathogens. During the 2-year study period, 1443 positive blood culture cases were identified, including 265 suspected cases of contamination. The overall DASC, DASC/patient, DOT, DOT/patient, and DASC/DOT metrics were 226,626; 157.1; 28,778; 19.9; and 7.9, respectively. A strong correlation was observed between DASC and DOT, as well as DASC/patient and DOT/patient. Conversely, DASC/DOT had no correlation with other metrics. The combination of DASC and DOT would be a useful benchmark for the overuse and misuse evaluation of antimicrobial therapy in BSIs. Notably, DASC/DOT would be a robust metric to evaluate the antibiotic spectrum that was selected for patients with BSIs.

Background: Influenza viruses are an important cause of respiratory infections across all age groups. Information on occurrence and magnitude of influenza virus infections in different populations in Kenya however remains scanty, compromising estimation of influenza disease burden. This study examined influenza infection in an urban high-income setting in Nairobi to establish its prevalence and activity of influenza viruses, and evaluated diagnostic performance of a rapid influenza diagnostic test., Methodology: A cross-sectional hospital-based study was conducted in six private health facilities located within high-income residential areas in Nairobi from January 2019 to July 2020. Patients of all ages presenting with influenza-like illness (ILI) were recruited into the study. Detection of influenza virus was conducted using rapid diagnosis and reverse transcription-polymerase chain reaction (RT-PCR). Data were summarized using descriptive statistics and tests of association. Sensitivity, specificity and area under receiver operating characteristics curve was calculated to establish diagnostic accuracy of the rapid diagnosis test., Results: The study recruited 125 participants with signs and symptoms of ILI, of whom 21 (16.8%) were positive for influenza viruses. Of all the influenza-positive cases, 17 (81.0%) were influenza type A of which 70.6% were pandemic H1N1 (A/H1N1 2009). Highest detection was observed among children aged 5-10 years. Influenza virus mostly circulated during the second half of the year, and fever, general fatigue and muscular and joint pain were significantly observed among participants with influenza virus. Sensitivity and specificity of the diagnostic test was 95% (95% confidence interval 75.1-99.9) and 100% (95% confidence interval 96.5-100.0), respectively., Conclusions: Findings of this study shows continuous but variable activity of influenza virus throughout the year in this population, with substantial disease burden. The findings highlight the need for continuous epidemiologic surveillance including genetic surveillance to monitor activity and generate data to inform vaccine introduction or development, and other interventions., (© 2022. The Author(s).)

Antimicrobial stewardship (AS) intervention strategy is a critical process in promoting appropriate antibiotic use, thus preventing unnecessarily prolonged therapy and reducing antimicrobial resistance (AMR). Although limiting unnecessary carbapenem use by AS intervention is speculated to reduce AMR, there is a lack of specific data on the efficacy of AS team (AST) intervention regarding carbapenem-resistant Pseudomonas aeruginosa (CRPA). Consequently, this study aimed to evaluate the impact of our AS strategy on carbapenem use and CRPA. The AS intervention strategy was launched in July 2017 and consisted of daily audits and feedback on carbapenem use. We evaluated the 4-year prescription trend, including the rate of switching to other antimicrobials, and the rate of CRPA and the days of therapy required prior to and after the beginning of the AST intervention. The rate of switching to narrow-spectrum antibiotics and the discontinuation of carbapenem treatment were significantly higher in the pre-intervention period compared with the post-intervention period. (7.0% vs. 14.5%; p<0.001; 54.1% vs. 50.9%; p=0.027). However, there were no significant differences in the rate of CRPA prior to and after the beginning of the AST intervention. Furthermore, there was no correlation found between consumption and resistance rate (Pearson's r=0.123). Our results suggest that it is extremely important for AST to promote de-escalation and reduce unnecessary use, while the combination of process and outcome indicators other than antimicrobial consumption and resistance rate are required for the evaluation of the AS programs.

Background: A characteristic feature of SARS-CoV-2 is its ability to transmit from pre- or asymptomatic patients, complicating the tracing of infection pathways and causing outbreaks. Despite several reports that whole genome sequencing (WGS) and haplotype networks are useful for epidemiologic analysis, little is known about their use in nosocomial infections., Aim: We aimed to demonstrate the advantages of genetic epidemiology in identifying the link in nosocomial infection by comparing single nucleotide variations (SNVs) of isolates from patients associated with an outbreak in Showa University Hospital., Methods: We used specimens from 32 patients in whom COVID-19 had been diagnosed using clinical reverse transcription-polymerase chain reaction tests. RNA of SARS-CoV-2 from specimens was reverse-transcribed and analysed using WGS. SNVs were extracted and used for lineage determination, phylogenetic tree analysis, and median-joining analysis., Findings: The lineage of SARS-CoV-2 that was associated with outbreak in Showa University Hospital was B.1.1.214, which was consistent with that found in the Kanto metropolitan area during the same period. Consistent with canonical epidemiological observations, haplotype network analysis was successful for the classification of patients. Additionally, phylogenetic tree analysis revealed three independent introductions of the virus into the hospital during the outbreak. Further, median-joining analysis indicated that four patients were directly infected by any of the others in the same cluster., Conclusion: Genetic epidemiology with WGS and haplotype networks is useful for tracing transmission and optimizing prevention strategies in nosocomial outbreaks., (© 2021 The Authors.)

Invasive trichosporonosis is a rare and lethal fungal infection that occurs in immunocompromised patients. Breakthrough trichosporonosis can occur in patients treated with echinocandins since Trichosporon spp. are resistant to these antifungal agents. We report a case of breakthrough Trichosporon asahii fungemia. A 62-year-old Japanese woman with relapsed follicular lymphoma was treated empirically with broad-spectrum antibiotics and micafungin due to an intermittent fever during reinduction chemotherapy. After four cycles of anti-cancer chemotherapy, she experienced a high neutropenic fever and T. asahii was subsequently detected from a blood culture. The patient was not given voriconazole due to the contraindication for use with carbamazepine, and she was successfully treated with fluconazole plus liposomal amphotericin B without any serious complications. The combined therapy of fluconazole and liposomal amphotericin B may therefore be useful in treating T. asahii fungemia, especially in patients receiving antiepileptic agents.

The nationwide surveillance on antimicrobial susceptibility of bacterial respiratory pathogens from the patients in Japan was conducted by the Japanese Society of Chemotherapy, the Japanese Association for Infectious Diseases, and the Japanese Society for Clinical Microbiology in 2016. The isolates were collected from clinical specimens obtained from well-diagnosed adult patients with respiratory tract infections during the period between February 2016 and August 2016 by three societies. Antimicrobial susceptibility testing was conducted at the central reference laboratory according to the method recommended by Clinical Laboratory Standards Institute. Susceptibility testing was evaluated in 1062 strains (143 Staphylococcus aureus, 210 Streptococcus pneumoniae, 17 Streptococcus pyogenes, 248 Haemophilus influenzae, 151 Moraxella catarrhalis, 134 Klebsiella pneumoniae, and 159 Pseudomonas aeruginosa). Ratio of methicillin-resistant S. aureus was 48.3%, and those of penicillin-susceptible S. pneumoniae was 99.5%. Among H. influenzae, 14.1% of them were found to be β-lactamase-producing ampicillin-resistant strains, and 41.1% to be β-lactamase-non-producing ampicillin-resistant strains. Extended spectrum β-lactamase-producing K. pneumoniae and multi-drug resistant P. aeruginosa with metallo β-lactamase were 4.5% and 0.6%, respectively., Competing Interests: Declaration of competing interest Katsunori Yanagihara received speaker honoraria from Taisho Toyama Pharmaceutical Co., Ltd., Pfizer Japan Inc., MSD K.K., Astellas Pharma Inc., Daiichi Sankyo Co., Ltd., Nippon Becton Dickinson Company, Ltd., and bioMerieux Japan Ltd., and received scholarship donations from Toyama Chemical Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Daiichi Sankyo Co., Ltd., Pfizer Japan Inc., MSD K.K., Taiho Pharmaceutical Co., Ltd., and FUJIFILM Toyama Chemical Co., Ltd. and received research funds from Nippon Becton Dickinson Company, Ltd., Shionogi, Kyorin Pharmaceutical Co., Ltd., Tosoh Corporation, Miyarisan Pharmaceutical Co., Ltd., and FUJIFILM Toyama Chemical Co., Ltd. Tetsuya Matsumoto received speaker honoraria from MSD K·K., and Pfizer Japan Inc. Makoto Miki received speaker honoraria from Kyorin Pharmaceutical Co., Ltd. Yoshitomo Morinaga received research funds from Nippon Becton Dickinson Company, Ltd., Shionogi & Co., Ltd., Kyorin Pharmaceutical Co., Ltd., Tosoh Corporation, Miyarisan Pharmaceutical Co., Ltd., Roche Diagnostics K·K., Beckman Coulter Inc., Parexel International Co., Ltd., and FUJIFILM Toyama Chemical Co., Ltd. Issei Tokimatsu received scholarship donations from Astellas Pharma Inc., Daiichi Sankyo Co., Ltd., and Shionogi & Co., Ltd. Hiroshi Kiyota have received scholarship donations from Taisho Toyama Pharmaceutical Co., Ltd., Toyama Chemical Co., Ltd., Daiichi Sankyo Co., Ltd., Astellas Pharma Inc., Taiho Pharmaceutical Co., Ltd., and Sanofi K·K. Yoshihito Niki received speaker honoraria from Pfizer Japan Inc., MSD K·K., Astellas Pharma Inc., Taisho Toyama Pharmaceutical Co., Ltd., MSD K·K., Sumitomo Dainippon Pharma Co., Ltd., and Asahi Kasei Pharma Corporation, and received scholarship donations from Astellas Pharma Inc., Daiichi Sankyo Co., Ltd., Taiho Pharmaceutical Co., Ltd., MSD K·K., and Shionogi & Co., Ltd. Takahiro Takuma received scholarship donations from Astellas Pharma Inc., Daiichi Sankyo Co., Ltd., and Shionogi & Co., Ltd. Nobuki Aoki received speaker honoraria from Kyorin Pharmaceutical Co., Ltd. Yoshihiro Yamamoto received research fund from Pfizer Japan Inc. Yoshitsugu Iinuma received speaker honoraria from MSD K·K. Atsushi Nakamura received speaker honoraria from MSD K·K., Kyorin Pharmaceutical Co., Ltd., and Astellas Pharma Inc. Hiroshi Kakeya received speaker honoraria from MSD K·K., Pfizer Japan Inc., Sumitomo Dainippon Pharma Co., Ltd., and Astellas Pharma Inc. Koichiro Yoshida received speaker honoraria from MSD K·K. Junichi Kadota received speaker honoraria from MSD K·K., Nippon Boehringer Ingelheim Co., Ltd., and Astrazeneca Co., Ltd., and received research funds from Taisho Toyama Pharmaceutical Co., Ltd., MSD K·K., and Nippon Boehringer Ingelheim Co., Ltd., and received scholarship donation from Daiichi Sankyo Co., Ltd., (Copyright © 2020. Published by Elsevier Ltd.)

Background: There are limited data for direct comparisons of the efficacy of oral itraconazole (ITCZ) and oral voriconazole (VRCZ) therapy in the treatment of chronic pulmonary aspergillosis (CPA)., Methods: We conducted a retrospective, follow-up, observational study of CPA patients enrolled in 2 previous multicenter trials., Results: Of the 273 CPA patients, 59 and 101 patients started maintenance therapy with oral ITCZ and oral VRCZ, respectively, just after the end of acute intravenous therapy in each trial. At the end of the observation period in this follow-up study (median observation period, 731 days), the percentage of patients who showed improvement was lower in the ITCZ group than in the VRCZ group (18.2% vs 40.0%). However, after including stable patients, the percentages were 50.9% and 52.6%, respectively, in the ITCZ and VRCZ groups, which were not significantly different (P = .652). Multivariable Cox regression analysis showed no significant influence of the choice of initial maintenance treatment (ITCZ or VRCZ) on overall mortality as well as CPA-associated mortality. Multivariable logistic regression showed that oral ITCZ selection for initial maintenance therapy was an independent risk factor for hospital readmission and switching to other antifungal agents (odds ratio [OR], 3.1; 95% confidence interval [CI], 1.3-7.5 and OR, 5.7; 95% CI, 2.0-15.7, respectively)., Conclusions: Oral VRCZ for initial maintenance therapy showed better effectiveness than oral ITCZ for clinical improvement in CPA patients. There was no difference in crude mortality between initial maintenance therapy with VRCZ and ITCZ, especially in elderly CPA patients., Clinical Trials Registration: UMIN000007055., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background De-escalation therapy is recommended as an effective antibiotic treatment strategy for several infectious diseases. While there is limited evidence supporting its clinical and cost-effective outcomes in patients with community-acquired bacteremic pneumonia, there is no evidence in patients with nonbacteremic pneumonia. Objective This study aimed to evaluate the antibiotic costs in patients who did and did not receive de-escalation therapy, based on the 2017 Japanese guidelines for the management of community-acquired nonbacteremic pneumococcal pneumonia of the Japanese Respiratory Society (JRS). Setting Kobe university hospital, Japan. Methods A retrospective case series review including antibiotic use and length of hospital stay was conducted using the medical records from April 2008 to May 2019 at a university hospital in Japan. Main outcome measure Impact of antibiotic de-escalation therapy on the antibiotic costs. Results Among 55 patients who were eligible, the treating physicians de-escalated antibiotics in 28 (51%). The differences in the median length of hospital stay and the incidence of adverse drug reactions between the two groups were not statistically significant (p = 0.67 and 1.0, respectively). However, the median total antibiotic cost per infected patient in the de-escalated group was significantly lower than that in the non-de-escalated group [$269.8 ($195-$389) vs. $420.5 ($221-$799), p = 0.048]. Conclusion Antibiotic de-escalation based on the 2017 JRS guidelines leads to a reduction in total antibiotic costs for the management of community-acquired nonbacteremic pneumococcal pneumonia.

Purpose: This study aimed to evaluate the efficacy of an educational intervention on reducing the inappropriate use of oral third-generation cephalosporins, the prevalence of resistant bacteria, and clinical outcomes., Methods: A before-after study was conducted to compare the data for 1 year before and after intervention at a Japanese university hospital. Educational intervention included lectures for all medical staff on oral antibiotics and educational meetings with each medical department. The primary outcome was the use of oral third-generation cephalosporins in inpatients as measured by the monthly median days of therapy (DOTs) per 1000 patient days. Secondary outcomes included the use of each oral antibiotic in inpatients and outpatients, proportion of β-lactamase-nonproducing ampicillin-resistant Haemophilus influenzae (BLNAR), penicillin-resistant Streptococcus pneumoniae (PRSP) and extended-spectrum β-lactamase producing Escherichia coli (ESBLEC), the incidence of hospital-acquired Clostridioides difficile infection (HA-CDI), and hospital mortality., Results: The use of oral third-generation cephalosporins in inpatients was significantly decreased after intervention [DOTs (interquartile range): 24.2 (23.5-25.1) vs. 3.7 (0.0-7.1), P < 0.001], and the value in outpatients was also decreased significantly. The use of fluoroquinolones and macrolides did not increase after intervention. The proportion of BLNAR, PRSP and ESBLEC did not change significantly during the study period. The incidence of HA-CDI was significantly decreased, and hospital mortality did not change after intervention., Conclusion: Educational intervention was effective in reducing the use of oral third-generation cephalosporins without increasing the use of broad-spectrum antibiotics and worsening clinical outcome. The prevalence of resistant bacteria did not change during the study period.

Background: The incidence of ocular candidiasis (OC) in patients with candidemia varies across different reports, and the issue of whether routine ophthalmoscopy improves outcomes has been raised. This study investigated the incidence of OC and evaluate whether the extent of OC impacts the clinical outcomes., Methods: This retrospective study included non-neutropenic patients with candidemia who underwent treatment at one of 15 medical centers between 2010 and 2016. Chorioretinitis without other possible causes for the ocular lesions and endophthalmitis was classified as a probable OC. If signs of chorioretinitis were observed in patients with a systemic disease that causes similar ocular lesions, they were classified as a possible OC., Results: In total, 781 of 1089 patients with candidemia underwent an ophthalmic examination. The prevalence of OC was 19.5%. The time from the collection of a positive blood culture to the initial ophthalmic examination was 5.0 ± 3.9 days in patients with OC. The leading isolate was Candida albicans (77.9%). Possible OC was associated with unsuccessful treatments (resolution of ocular findings) (odds ratio: 0.354, 95% confidence interval: 0.141-0.887), indicating an overdiagnosis in patients with a possible OC. If these patients were excluded, the incidence fell to 12.8%. Endophthalmitis and/or macular involvement, both of which require aggressive therapy, were detected in 43.1% of patients; a significantly higher incidence of visual symptoms was observed in these patients., Conclusion: Even when early routine ophthalmic examinations were performed, a high incidence of advanced ocular lesions was observed. These results suggest that routine ophthalmic examinations are still warranted in patients with candidemia., Competing Interests: Y. Takesue has received grant support from Sumitomo Dainippon Pharma Co., Ltd., and Shionogi & Co., Ltd., and payment for lectures from Astellas Pharma Inc., and MSD Japan. T Miyazaki has received research grants from Astellas Pharma Inc., Pfizer Japan Inc., MSD Japan, and Asahi Kasei Pharma Co. H. Mikamo has received grant support from Sumitomo Dainippon Pharma Co., Ltd., Astellas Pharma Inc., Pfizer Japan Inc., MSD Japan, and payment for lectures from MSD Japan, Astellas Pharma Inc., and Sumitomo Dainippon Pharma Co., Ltd. Y. Yamagishi has received grant support from Pfizer Japan Inc., MSD Japan, Astellas Pharma Inc., and Sumitomo Dainippon Pharma Co., Ltd., and payment for lectures from Sumitomo Dainippon Pharma Co., Ltd., and MSD Japan. K. Yoshida has received payment for lectures from MSD Japan, Pfizer Japan Inc., and Sumitomo Dainippon Pharma Co., Ltd. H. Kakeya has received grant support from Pfizer Japan Inc., MSD Japan, Astellas Pharma Inc., and Sumitomo Dainippon Pharma Co., Ltd. Other authors have no conflict of interest to declare. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Objectives: To examine the clinical risk factors for death within 30 days of diagnosis of Pseudomonas aeruginosa-causing bacteremia after a urinary tract infection., Methods: A total of 62 patients with Pseudomonas aeruginosa isolated from both urine and blood at the same episode from January 2009 to December 2016 were enrolled in the present study. We retrospectively investigated clinical risk factors for death by comparison between surviving patients and those who died within 30 days after diagnosis of P. aeruginosa bacteremia. The comparison for risk factors for bacteremia-related death included 31 categories, such as age, laboratory data, underlying diseases, clinical history, history of surgery, care in the intensive care unit, P. aeruginosa susceptibility to the antibiotics used at the time of bacteremia diagnosis and consultation with urological department., Results: The study included 48 men and 14 women aged 71.3 ± 10.4 years. Nine patients (14.5%) died of P. aeruginosa bacteremia. Statistical analysis showed that non-survivors had significantly lower albumin levels than survivors (2.07 ± 0.62 vs 2.62 ± 0.65; P = 0.023). The non-survivors had significantly higher rates of ventilator use, history of heart disease, septic shock and lower rates of consultation with urological departments after diagnosis (P < 0.05)., Conclusions: Patients with bacteremia complicating urinary infection by P. aeruginosa have a low death rate. Earlier intervention by urologists might improve patients' outcome. Lower albumin levels, ventilator use, history of heart disease and septic shock are factors associated with higher mortality rate., (© 2018 The Japanese Urological Association.)

Pseudomonas aeruginosa, responsible for serious nosocomial-acquired infections, possesses intrinsic antibiotic resistance mechanisms and commonly exhibits multidrug resistance. Here, we report the evolving resistance profiles of strains isolated from the sputum of a patient being treated for repeated P. aeruginosa infections following cancer resection. Whole genome sequencing of six isolates obtained over a 2-month period revealed two key single nucleotide polymorphisms in the mexR and gyrB genes that affected efflux pump expression and antimicrobial resistance., (Copyright © 2018. Published by Elsevier Ltd.)

Diffuse panbronchiolitis (DPB) is a progressive inflammatory airway disease characterized by a chronic cough, copious sputum expectation, dyspnea, and chronic sinusitis. Owing to the long-term treatment of low-dose macrolides, the prognosis has been remarkably improved. However, in some cases, patients are refractory to macrolides, and the subsequent treatment strategies are controversial. We herein present a patient with the onset of DPB during treatment with long-term, low-dose clarithromycin (CAM) for chronic sinusitis who was successfully treated by switching to long-term treatment with normal-dose CAM. We should recognize that DPB may develop in patients with chronic sinusitis despite treatment with a long-term, low-dose macrolide. We also propose that increasing the dose of macrolide may be a useful strategy for treating refractory patients., (Copyright © 2018. Published by Elsevier Ltd.)

Scopulariopsis alboflavescens is a soil saprophyte that is widely distributed in nature. Recently, there have been increasing number of reports of invasive infections with Scopulariopsis species in immunocompromised patients. In this report, we described an adult woman with acute myeloid leukemia and who developed S. alboflavescens pneumonia. Liposomal amphotericin B and voriconazole combination therapy was unsuccessful and the patient died because of pneumonia. Scopulariopsis is highly resistant to available antifungal agents and almost invariably fatal. This case report should alert clinicians to the importance of listing Scopulariopsis as a pathogenic fungus in immunocompromised patients.

We conducted a nationwide molecular epidemiological study of Clostridium difficile infection (CDI) in Japan investigated the correlation between the presence of binary toxin genes and CDI severity. This is the first report on molecular epidemiological analyses for CDI in multiple university hospitals in Japan, to our knowledge. We examined 124,484 hospitalized patients in 25 national and public university hospitals in Japan between December 2013 and March 2014, investigating antimicrobial susceptibilities and toxin-related genes for C. difficile isolates from stools. Epidemiological genetic typing was performed by PCR-ribotyping and repetitive sequence-based (rep)-PCR to examine the genetic similarities. The results detected toxin A-positive, toxin B-positive, binary toxin-negative (A + B + CDT - ) detected from 135 isolates (80.8%) and toxin A-negative, toxin B-positive, binary toxin-negative (A -  B + CDT - ) in 23 (13.8%). Toxin A-positive, toxin B-positive, and binary toxin-positive (A + B + CDT + ) were seen in 9 isolates (5.4%). Vancomycin (n = 81, 37.7%) or metronidazole (n = 88, 40.9%) therapies were undertaken in analyzed cases. Ribotypes detected from isolates were 017/subgroup 1, 070, 078, 126, 176, 449, 475/subgroup 1, 499, 451, 566 and newtypes. Rep-PCR classified 167 isolates into 28 cluster groups including 2-15 isolates. In addition, 2 pairs of strains isolated from different institutions belonged to the same clusters. Seven out of 9 (77.8%) of the patients with binary toxin producing strains had "mild to moderate" outcome in evaluated symptoms. In conclusion, we found that binary toxin did not show regional specificity and had no relevance to severity of CDI., (Copyright © 2018 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Purpose: Stenotrophomonas maltophilia has low pathogenicity potential, but if it causes bacteremia it can be fatal, because it has shown high resistance to many antibiotics and can be difficult to treat. Patient death from S. maltophilia bacteremia has increased since 2014 in our hospital. In this study, we investigated risk factors for death due to S. maltophilia bacteremia., Methods: Seventy patients from the hospital database with S. maltophilia bacteremia between January 2010 and July 2017 were investigated. We retrospectively analyzed risk factors including gender, age, wards, hospitalized duration, clinical history, devices, source of S. maltophilia identification, polymicrobial bacteremia, prior antimicrobial therapy, antimicrobial therapy after bacteremia, and resistance to antibiotics. The statistical analysis was performed to compare the period from 2010 to 2013 to from 2014 to 2017., Results: Comparing the 2010-2013 period to the 2014-2017 period, it revealed that history of hospitalization, identification of S. maltophilia from sputum, polymicrobial bacteremia, prior carbapenem use, and mortality was significantly different in S. maltophilia bacteremia (p = 0.028, p = 0.004, p < 0.001, p = 0.034, and p = 0.007, respectively). Comparison between non-survivors and survivors for 2010-2013 and 2014-2017 found ICU admission and ventilator use were seen more often in non-survivors (p = 0.030 vs p = 0.013 and p = 0.027 vs p = 0.010, respectively)., Conclusions: Our analyses showed increase in mortality from S. maltophilia bacteremia from 2014 to 2017, and that non-survivors had a higher frequency of ICU admission and ventilator use in both the 2010-2013 and 2014-2017 periods. There were more combination antimicrobial therapy cases after bacteremia in 2014-2017. Further prospective studies with larger numbers of patients should be undertaken for definitive conclusions., (Copyright © 2018 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Mycobacterium abscessus complex, including three subspecies-M. abscessus, M. massiliense, and M. bolletii-is resistant to a variety of antibiotics so limited treatment options are available. The susceptibility of these subspecies to antimicrobial agents depends in particular on the erm(41) sequevar and rrl mutations in the 23S rRNA, which are potentially related to clarithromycin (CLR) resistance. The purpose of this study was to carry out identification and molecular characterization of these subspecies based on variable number of tandem repeats (VNTR) analysis. Twenty-four M. abscessus complex strains were identified as M. abscessus and M. massiliense and these subspecies could be discriminated between based on their resistance to CLR, as determined by truncation or mutation of erm(41) or mutation of rrl, as illustrated by their VNTR patterns. In conclusion, we confirmed that the CLR susceptibility profiles could be differentiated according to the subspecies of M. abscessus complex strains by their VNTR patterns., (Copyright © 2018. Published by Elsevier Inc.)

Procaterol hydrochloride hydrate (procaterol) is a β 2 -adrenergic receptor agonist that induces a strong bronchodilatory effect. The procaterol dry powder inhaler (DPI) has been frequently used in patients with bronchial asthma or chronic obstructive pulmonary disease. We evaluated the bioequivalence and safety between the new procaterol DPI (new DPI) and the approved procaterol DPI (approved DPI). This study was a randomized, double-blind, double-dummy, crossover comparison to evaluate the pharmacodynamic equivalence of the new DPI and the approved DPI in patients with bronchial asthma. Primary efficacy variables were area under the concentration-time curve (AUC) forced expiratory volume in the first second (FEV 1 )/h and maximum FEV 1 during the 480-minute measurement period. Patients were divided into 2 groups, New-DPI-First (n = 8) and Approved-DPI-First (n = 8), according to the investigational medical product that was administered first. Patients inhaled 20 μg of procaterol in each period. FEV 1 was measured by a spirometer at predose and at 15, 30, 60, 90, 120, 180, 240, 360, and 480 minutes after each investigational medical product administration. Equivalence was evaluated by confirming that the 2-sided 90%CIs for the difference between the new and the approved DPI in means of AUC (FEV 1 )/h and maximum FEV 1 were within the acceptance criteria of -0.15 to 0.15 L. The difference in means of AUC (FEV 1 )/h and maximum FEV 1 was 0.041 L and 0.033 L, respectively, and the 90%CI was 0.004 to 0.078 L and -0.008 to 0.074 L, respectively. These CIs were both within the acceptance criteria. The new DPI was assessed as being bioequivalent to the approved DPI., (© 2017 The Authors. Clinical Pharmacology in Drug Development Published by Wiley Periodicals, Inc. on behalf of The American College of Clinical Pharmacology.)

Objective: To evaluate the long-term effects of comprehensive antibiotic stewardship programs (ASPs) on antibiotic use, antimicrobial-resistant bacteria, and clinical outcomes., Design: Before-after study., Setting: National university hospital with 934 beds., Intervention: Implementation in March 2010 of a comprehensive ASPs including, among other strategies, weekly prospective audit and feedback with multidisciplinary collaboration., Methods: 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., Results: The mean monthly use of antipseudomonal antibiotics significantly decreased in 2011 and after as compared with 2009. Susceptibility to levofloxacin was significantly increased from 2009 to 2016 (P = 0.01 for trend). Its susceptibility to other antibiotics remained over 84% and did not change significantly during the study period. The proportion of patients isolated MRSA and the incidence of MRSA decreased significantly from 2009 to 2016 (P < 0.001 and = 0.02 for trend, respectively). There were no significant changes in the 30-day mortality attributable to bacteremia during the study period (P = 0.57 for trend)., Conclusion: The comprehensive ASPs had long-term efficacy for reducing the use of the targeted broad-spectrum antibiotics, maintaining the antibiotic susceptibility of P. aeruginosa, and decreasing the prevalence of MRSA, without adversely affecting clinical outcome.

Background: Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) contributes to rapid identification of pathogens in the clinic but has not yet performed especially well for Gram-positive cocci (GPC) causing complicated urinary tract infection (UTI). The goal of this study was to investigate the possible clinical use of MALDI-TOF MS as a rapid method for bacterial identification directly from urine in complicated UTI., Methods: MALDI-TOF MS was applied to urine samples gathered from 142 suspected complicated UTI patients in 2015-2017. We modified the standard procedure (Method 1) for sample preparation by adding an initial 10 minutes of ultrasonication followed by centrifugation at 500 g for 1 minutes to remove debris such as epithelial cells and leukocytes from the urine (Method 2)., Results: In 133 urine culture-positive bacteria, the rate of corresponded with urine culture in GPC by MALDI-TOF MS in urine with standard sample preparation (Method 1) was 16.7%, but the modified sample preparation (Method 2) significantly improved that rate to 52.2% (P=.045). Method 2 also improved the identification accuracy for Gram-negative rods (GNR) from 77.1% to 94.2% (P=.022). The modified Method 2 significantly improved the average MALDI score from 1.408±0.153 to 2.166±0.045 (P=.000) for GPC and slightly improved the score from 2.107±0.061 to 2.164±0.037 for GNR., Conclusion: The modified sample preparation for MALDI-TOF MS can improve identification accuracy for complicated UTI causative bacteria. This simple modification offers a rapid and accurate routine diagnosis for UTI, and may possibly be a substitute for urine cultures., (© 2017 Wiley Periodicals, Inc.)

In this study, we compared the antibiotic use, urinary tract infection-causative bacteria and their antibiotic susceptibilities among four hospitals with different backgrounds and regions in Japan in 2014. Frequency of antibiotic use (antibiotic use density: AUD/all AUD) were: ampicillin: 0.21-20.3 (median: 1.6) and cefazolin: 0.8-34.2 (2.5), representatively. The antibiotic resistant rates of Escherichia coli were ampicillin: 1.1-52.3% (median: 51.8%), piperacillin: 47.9-49.1% (48.0%), cefazolin: 23.2-34.1% (28.9%), levofloxacin: 36.6-43.8% (40.2%).We found that there were significant correlations (1) between antibiotic resistance of E. coli and annual total amount of antibiotic use (p = 0.017), annual number of days of antibiotic use (p = 0.002) and days of therapy (DOT, p = 0.002), and (2) between antibiotic resistance of extended-spectrum β-lactamase-producing bacteria and annual number of days of antibiotic use (p = 0.004) and DOT (p = 0.004) in a rehabilitation hospital. These results suggested that more antibiotic uses could lead to antibiotic resistances. Further analyses with more number of data are being undertaken.

Introduction: Urosepsis is a severe infection that can cause shock afterwards. The purpose of this study is to investigate the clinical and bacterial risk factors for shock in those cases with urosepsis caused by urinary tract infection in a multicentre study., Methods: Our study included 77 consecutive urosepsis cases from four hospitals . We examined factors such as patient characteristics, underlying disease, serum white blood cell (WBC) count, platelet count, C-reactive protein (CRP) level at the time of diagnosis of urosepsis, urinary tract occlusion, causative bacteria, and bacterial antibiotic susceptibilities. Statistical analyses were performed to assess the potential risk factors for shock during the clinical course of urosepsis by a multivariate analysis., Results: We had 38 male and 39 female patients aged 25-104 (median 73). Underlying diseases included cancers (n=22, 28.6 %) and diabetes mellitus (n=17, 22.1 %). Positive blood culture was seen in 74 cases; these involved 88 bacterial strains, of which Escherichia coli was the most common (34 strains, 38.6 %). There were 31 cases with shock (40.3 %) and multivariate analyses demonstrated that serum CRP was the only clinical risk factor for shock due to urosepsis., Conclusions: Our study demonstrated that serum CRP was a risk factor for shock during urosepsis in a multicentre analysis. Further prospective studies with a greater number of patients are needed to draw more definitive conclusions.

Carbapenem-resistant Enterobacteriaceae (CRE) are increasing globally. Particularly, carbapenemase-producing Enterobacteriaceae (CPE) are of concern. Rapid and accurate detection of these strains is critical for appropriate antimicrobial use and hospital infection control. In the present study, criteria for CPE screening were examined using a carbapenem susceptibility disk. Carbapenemase producers showed minimal inhibition zones for faropenem (5 μg): 6-12 mm (mean: 6.9 mm). Some strains with the IMP-6 genotype showed inhibition zones of >30 mm for imipenem (10 μg) and biapenem (10 μg). All strains that formed inhibition zones for FRPM had the IMP-6 genotype. The cut off values of carbapenemase-producers, determined by ROC analysis, were 12 mm for FRPM, 24 mm for meropenem (10 μg), 29 mm for BIPM, 25 mm for doripenem (10 μg), 26 mm for IPM, and 24 mm for panipenem (10 μg). Thus, the sensitivity was the highest (100%) for FRPM. Specificities were 93.44% for MEPM and DRPM and 85.25% for FRPM. Consequently, a drug sensitivity test using FRPM (5 μg) disks facilitates simple and accurate CPE screening.

Objectives To investigate the efficacy of oral moxifloxacin (MFLX) as a treatment for pneumonia in hemodialysis (HD) patients and the pharmacokinetic (PK) profile of MFLX after oral administration. Methods Thirteen adult patients who required HD due to chronic renal failure were enrolled in the present study, which was performed to investigate the treatment of community-acquired pneumonia in HD patients. A standard dose of MFLX (400 mg, once daily) was administered. The therapy was continued, discontinued, or switched to another antibiotic depending on the response of the pneumonia to MFLX. A population PK model was developed using the post-hoc method. Results In total, 13 HD patients with pneumonia (male, n=7; female, n=6) were enrolled in the present study. The evaluation on the 3rd day showed that treatment was successful in 11 patients (84.6%) and that 10 patients were cured (76.9%). In the one case in which MFLX treatment failed, the patient was cured by switching to ceftriaxone (CTRX) (2 g, intravenously) plus levofloxacin (LVFX) (250 mg, orally). The causative bacterium in this male patient was P. aeruginosa. It did not display resistance to fluoroquinolones. One patient had liver dysfunction due to MFLX. The estimated PK parameters of MFLX were as follows: AUC 0→24 , 61.04±17.74 μg h/mL; C max , 5.25±1.12 μg/mL; and C trough , 1.15±0.45 μg/mL. The PK parameters of MFLX among the patients in whom adverse events occurred or in whom a cure was not achieved did not differ from those of the other patients to a statistically significant extent. Conclusion MFLX showed good efficacy and safety in HD patients with community-acquired pneumonia and the results of the PK analysis were favorable. Further prospective studies with larger numbers of patients will be needed to draw definitive conclusions.

The mechanisms of azole resistance in Trichosporon asahii have not yet been fully clarified. We previously showed that T. asahii has the ERG11 gene, coding lanosterol 14-α-demethylase (Erg11 protein; Erg11p), which is the primary target of azoles. A single amino acid substitution at G453R in Erg11p was found to induce changes in the affinity of this enzyme for azoles, especially fluconazole, in vitro. In the present study, we investigated the DNA sequences of the ERG11 gene using six different strains of clinically isolated T. asahii that were highly resistant to multi-azoles, including fluconazole, itraconazole, and voriconazole. All of the T. asahii strains had a point mutation (G448A) that caused a single amino acid substitution at G150S in Erg11p. This amino acid is highly conserved among major fungal pathogens. We identified a new point mutation in the ERG11 gene that is common to clinically isolated azole-resistant T. asahii strains, suggesting that this mutation is associated with the multi-azole resistance of T. asahii.

Introduction: This study examined the risk factors for initial treatment failure in renal or retroperitoneal abscess as a multicenter study., Materials and Methods: This retrospective analysis investigated consecutive patients with renal or retroperitoneal abscess who were hospitalized in Japan. The outcomes of these patients were classified into "cured" and "failure or recurrence." The potential clinical risk factors examined were abscess size, diabetes mellitus, major organ failure, laboratory data, fever, drainage, and causative organisms, for instance., Results: Of the 74 patients, 40 (54.1%) were diagnosed with renal abscess and 34 (45.9%) with retroperitoneal abscess, 51 (68.9%) were cured by initial treatments, and 23 (31.1%) underwent failure or relapse; 33 (44.6%) were men and 41 (55.4%) were women. In detail, 36 patients were cured by conservative therapy only. Our multivariate analysis data showed that renal failure was the only significant factor for initial treatment failure (p = 0.0281)., Conclusions: Our multivariate analysis showed that renal failure was a significant risk factor for initial treatment failure or recurrence., (© 2017 S. Karger AG, Basel.)

Reactivation of latent infection is considered to be the main mechanism underlying the development of Pneumocystis pneumonia in immunosuppressed patients. We retrospectively assessed the effects of prophylactic administration of sulfamethoxazole-trimethoprim on the development of P. pneumonia and airway colonization with P. jirovecii in patients undergoing examinations to diagnose or rule out P. pneumonia. Polymerase chain reaction was performed to detect P. jirovecii in bronchoalveolar lavage fluid or sputum of 60 consecutive patients between 2004 and 2012. No patients who received the prophylactic administration of sulfamethoxazole-trimethoprim (n = 10) developed P. pneumonia or demonstrated airway colonization with P. jirovecii, and none of the patients who developed P. pneumonia (n = 11) or showed colonization (n = 9) had received prophylactic treatment. Furthermore, 20 (40%) of 50 patients without prophylactic treatment showed positive results on the P. jirovecii DNA polymerase chain reaction, but all 10 patients who had prophylactic treatment showed negative results (Fisher's exact test, P = 0.02). Therefore, the prophylactic administration of sulfamethoxazole-trimethoprim has potential to be effective in preventing P. pneumonia as well as eliminating airway colonization with P. jirovecii. Further studies targeting large cohorts of patients with a variety of underlying diseases are required to develop recommendations regarding the prophylactic administration of sulfamethoxazole-trimethoprim.

There are several mechanisms for antibiotic-resistant Pseudomonas aeruginosa. The purpose of this study is to investigate the association between the expression of efflux pump-coding genes and antibiotic resistance in P. aeruginosa causing urinary tract infections (UTIs). We extracted the RNA from 105 clinical strains of P. aeruginosa isolated from UTI patients with full data on antibiotic MICs and assayed real-time quantitative reverse-transcription PCR. We investigated the gene expressions of four resistance nodulation cell division-type multi-drug efflux pump systems (MexAB-OprM, MexCD-OprJ, MexEF-OprN and MexXY(-OprA)) and the correlation of the MICs of nine antibiotics, risk factors and antibiotic resistance-related genes with expressions of mexB, mexC, mexE and mexY. Multivariate statistical data demonstrated a significant relationship between increased expression of mexB or mexC and complicated UTI (Odds ratio=8.03, P<0.001 and Odds ratio=8.86, P=0.032, respectively). We also found a significant association between the increased expression of mexC and resistance to levofloxacin (LVFX) (Odds ratio=4.48, P=0.035). In conclusion, increased expression of mexC leads to LVFX resistance in P. aeruginosa causing UTI. These results contribute to our knowledge of the efflux pump system and antibiotic resistance.

Purpose: To investigate the optimal dose of vancomycin (VCM) for methicillin-resistant Staphylococcus aureus infections in the urological patients including renal dysfunction., Methods: We had 143 sets of available data from the consecutive patients treated in the urological department for analysis in VCM dose, VCM trough and estimated glomerular filtration rate: eGFR at VCM trough examination. Patients were classified according to eGFR level, and we calculated the regression line between VCM dose and VCM trough accordingly., Results: Median VCM dose were 1000 (range 500-3500) mg per day, the VCM trough was 15.6 ± 7.89 μg/ml, and eGFR was 61.1 ± 27.2 ml/min/1.73 m(2). Our regression analysis (x axis: VCM dose (mg) and y axis: VCM trough (μg/ml) was statistically significant in the group with eGFR of 30-60 ml/min/1.73 m(2) (y = 26.103x + 481.7; r (2) = 0.1291) and the group with eGFR of 60-90 ml/min/1.73 m(2) (y = 48.891x + 350.75; r (2) = 0.2561) in both with (p = 0.021 and 0.035, respectively) or without (p = 0.012 and 0.004, respectively) adjustments by body weight for VCM doses., Conclusion: These data showed that the optimal dose of VCM varied according to the eGFR value in consecutive urological patients with various renal functions.

Background: The target trough concentration of vancomycin in patients with febrile neutropenia has not been reported. The aim of this study was to estimate the target trough concentration for febrile neutropenia in patients with hematological malignancy., Methods: In this retrospective, single-center, observational cohort study, 63 hospitalized patients with hematological malignancy who were treated with vancomycin for febrile neutropenia due to bacteriologically documented or presumptive Gram-positive infections were analyzed., Results: A significant difference in the first trough concentration of vancomycin was observed between the response and non-response groups, and between the nephrotoxicity and non-nephrotoxicity groups. Multiple logistic regression analyses identified the first trough concentration as the only independent variable associated with clinical efficacy and nephrotoxicity of vancomycin. The areas under the ROC curves were 0.72 and 0.83 for clinical efficacy and nephrotoxicity, respectively. The cut-off values of the first trough concentration were 11.1 μg/ml for clinical efficacy (sensitivity 60%, specificity 87%) and 11.9 μg/ml for nephrotoxicity (sensitivity 77%, specificity 82%)., Conclusions: These results suggest a relationship of trough vancomycin concentration with clinical efficacy and incidence of nephrotoxicity. We propose a target trough vancomycin concentration of around 11.5 μg/ml for febrile neutropenia in patients with hematological malignancy., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Most cases of deep-seated trichosporonosis develop in patients with neutropenia, but it has recently been reported that breakthrough infections with Trichosporon species can develop during the use of candin family of antifungal agents. This is due to the primary resistance of the causal fungus, Trichosporon asahii (T. asahii), to the candin agents. On the other hand, there has been a case report of infection with Trichosporon that presented high-level resistance to the azole family of antifungal agents. Therefore, the possibility that the frequent use of azole agents may lead to secondary resistance to these agents is a cause for concern. Since trichosporonosis is a relatively rare infectious disease, there has been no established breakpoint for this fungus to various antifungal agents, wherein we cannot precisely confirm its sensitivity or resistance to the agents. However, our experiment demonstrated one of the processes for acquired drug resistance, wherein the minimal inhibitory concentration of fluconazole for T. asahii was markedly elevated after its long-term in vitro exposure to the drug. Although the mechanisms for drug-resistance of Trichosporon species are unknown, it is supposed that they are the same as the mechanisms found in Candida and Aspergillus species, namely, modification of target molecules or decrease of access to the molecules. Since cases of trichosporonosis are likely to increase in the future, we believe that there is an urgent need to establish the breakpoint for T. asahii based on large-scale drug sensitivity tests, as well as to elucidate its drug-resistance mechanisms.

The guideline for the "Clinical Evaluation Methods for New Antimicrobial Agents to Treat Respiratory Infections (Second Version)," published by the Japanese Society of Chemotherapy in January 2012, was proposed to achieve consistency with FDA guidelines based on the concept of clinical evaluation used in Japan. We assessed the clinical efficacy of levofloxacin (LVFX) in patients with bacterial pneumonia according to this new set of guidelines for the first time. The clinical efficacy of LVFX in patients with community-acquired pneumonia (CAP) and healthcare-associated pneumonia (HCAP) at the test of cure (TOC) was 87.5% (56/64) and 85.7% (6/7), respectively, with an overall efficacy of 87.3% (62/71). The clinical efficacy of LVFX at TOC was as follows: intravenous 81.5% (22/27), oral 88.9% (24/27), switchover from intravenous to oral administration 100% (10/10), respectively. The bacterial eradication rate in the patients with CAP and HCAP and overall efficacy at the end of therapy (EOT) was 95.3% (41/43), 100.0% (4/4) and 95.7% (45/47), respectively. The frequent causative bacterial strains included Streptococcus pneumoniae (18), Haemophilus influenzae (14) and Moraxella catarrhalis (6). The incidence of adverse reactions in the patients whose safety was evaluated was 15.7% (14/89), similar to that previously reported. The clinical efficacy of LVFX at the early phase, EOT and TOC of CAP, as assessed according to the new and former guidelines, was 70.4% (38/54) and 27.8% (15/54), 87.0% (60/69) and 79.1% (53/67), 87.5% (56/64) and 88.1% (59/67), respectively, with no significant differences. Therefore, the new efficacy evaluation method can be used in exchange for the former evaluation method., (Copyright © 2014 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Exophiala dermatitidis pneumonia is extremely rare. Here we report a case of E. dermatitidis pneumonia successfully treated with long-term itraconazole therapy. A 63-year-old woman without a remarkable medical history developed a dry and chest pain. Chest radiographs revealed consolidation in the middle lobe of the lung. Cytologic examination by bronchoscopy showed filamentous fungi and E. dermatitidis was detected in the bronchoalveolar lavage fluid. After 5 months of itraconazole therapy, her symptoms improved and the area of consolidation diminished. Two weeks after discontinuing the itraconazole therapy, the area of consolidation reappeared. Itraconazole therapy was restarted and continued for 7 months. The abnormal shadow observed on the chest X-ray gradually diminished. Over a 27-month follow-up with periodic examination, there was no relapse and the patient had a favorable clinical course., (Copyright © 2014 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

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

Background: Teicoplanin (TEIC) is a glycopeptide currently used for the treatment of methicillin-resistant Staphylococcus aureus (MRSA). A plasma trough concentration (Cmin) of >20 mg/l should be used for severe infections. The aim of this study was to assess the efficacy, safety and use of Cmin >20 mg/l on day 4-6 in patients with complicated MRSA infections., Methods: Blood samples were drawn from the 41 included patients just before TEIC administration between day 4 and 6. The patients were divided into three groups (group A: >20 mg/l, group B: 10-20 mg/l and group C: <10 mg/l) based on their Cmin on day 4-6., Results: Differences in efficacy between the groups were significant, but differences in safety were not. The patients in group A required lower cumulative doses than those in either groups B or C., Conclusions: The optimal clinical efficacy and safety might be associated with TEIC Cmin on the fourth to sixth day., (© 2015 S. Karger AG, Basel.)

Aims: Idiopathic pulmonary fibrosis continues to be a devastating clinical disorder for which there are few therapeutic options, and the pathogenesis of this disease remains largely unknown. Statins are inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase in cholesterol biosynthesis, and they have been reported to exert pleiotropic effects on the cellular signaling involved in tissue inflammation and in organ fibrosis/remodeling. We examined the preventive effects of statins on fibrogenic mediator expression and production in normal human lung fibroblasts (NHLF)., Main Methods: NHLF were pretreated with 100nM pitavastatin or medium alone (control), and were then stimulated with transforming growth factor-β1 (TGF-β1). mRNA expression and protein secretion of several mediators from cells were analyzed by real-time polymerase chain reaction, enzyme-linked immunosorbent assay or multiplex assay., Key Findings: TGF-β1-induced expression or production of mediators, such as collagen-1, vascular endothelial growth factor and chemokine C-X-C motif ligand 8, in NHLF pretreated with pitavastatin was significantly suppressed with inhibition of Smad-3 phosphorylation, as compared to untreated controls. In addition, the inhibitory effects of pitavastatin were negated by addition of mevalonate., Significance: Pitavastatin appeared to inhibit TGF-β1-induced fibrogenic mediator production from lung fibroblasts via the mevalonic cascade. Although further evaluation of the signaling pathways for these phenomena is necessary, our results suggest the potential benefits of pitavastatin., (© 2013.)

The switch from intravenous to oral antibiotic therapy is recommended for treating hospitalized patients with community-acquired pneumonia (CAP). We performed a multicenter, randomized study to assess the benefit of switching from intravenous sulbactam/ampicillin (SBT/ABPC) to oral garenoxacin (GRNX) in patients with CAP. Among adult CAP patients who must be hospitalized for intravenous antibiotic treatment, those with Pneumonia Patient Outcomes Research Team (PORT) scores of II-IV (mild to moderate) were initially treated with intravenous SBT/ABPC (6 g/day) for 3 days. A total of 108 patients who fulfilled the inclusion criteria (improved respiratory symptoms, CRP < 15 mg/dl, adequately improved oral intake, fever ≤ 38 °C for ≥ 12 h), were divided into two groups based on the antibiotic administered, the GRNX (switch to GRNX 400 mg/day) and SBT/ABPC groups (continuous administration of SBT/ABPC), for 4 days. Improvement in clinical symptoms, chest radiographic findings, and clinical effectiveness were evaluated by a central review board. Improvement in clinical symptoms was 96.3 and 90.2% in the GRNX and SBT/ABPC groups, respectively. Improvement in chest radiographic findings was 94.4 and 90.2% and clinical effectiveness was 94.4 and 90.2% in the GRNX and SBT/ABPC groups, respectively. Microbiological efficacy was 90.9 and 69.2% in the GRNX and SBT/ABPC groups, respectively. There were no significant differences between the groups. Converting to GRNX was as effective as continuous SBT/ABPC treatment in mild to moderate CAP patients in whom initial intravenous antibiotic treatment was successful.

Background: Therapeutic drug monitoring (TDM) of voriconazole is important to optimize efficacy and to minimize toxicity and intolerance. In this study, we evaluated the effect of sustained high plasma trough concentration of voriconazole on the incidence of hepatotoxicity in hospitalized Japanese patients., Methods: Thirty-nine patients were divided into 3 groups according to trough concentrations in two consecutive TDMs: <4 μg/ml in the first TDM (group A, n=25), >4 μg/ml in the first and <4 μg/ml in the second TDM (group B, n=8), and >4 μg/ml in both first and second TDMs (group C, n=6)., Results: Incidences of hepatotoxicity in groups A, B and C were 16.0, 25.0 and 83.3%, and significant differences were observed between groups A and C and groups B and C. Multiple logistic regression analysis identified the classification into groups A, B and C as an independent variable of hepatotoxicity., Conclusions: These results suggest that sustained high trough concentration of voriconazole may increase the risk of hepatotoxicity, and decreasing trough concentration to <4 μg/ml by dose adjustment after the initial TDM may reduce the incidence of hepatotoxicity in patients treated with voriconazole., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Aim: Deaths from aspiration pneumonia in elderly patients are occasionally considered to be "death from age-related physical debility", because most aspiration pneumonias are a result of aging and lead to death without any definitive therapy. The aim of the present study was to assess physicians' attitudes toward the diagnosis of and actual description of "death from age-related physical debility" on death certificates for deceased patients with aspiration pneumonia., Methods: This study surveyed 62 Japanese physicians including 36 pulmonologists and 26 other physicians who treat patients with pneumonia. Their attitudes regarding consideration and actually recorded "death from age-related physical debility" for deceased patients with aspiration pneumonia were assessed by using anonymous questionnaires, which included the decision-making process and the necessity of detailed diagnostic criteria., Results: A total of 32 (52%) respondents had considered deceased patients with aspiration pneumonia to be "death from age-related physical debility", and 10 (16%) have actually stated this on the death certificate. Advanced age, bedridden status, inability of oral intake and disturbance of consciousness including dementia were major factors in their decision-making. A total of 34 (55%) of the respondent physicians wanted detailed criteria to be established., Conclusions: Physicians' attitudes toward the definition of "death from age-related physical debility" vary a great deal depending on the respondent. The description in death certificates therefore might inaccurately reflect the results of current mortality statistics in Japan., (© 2012 Japan Geriatrics Society.)