Published Papers - YAMAMOTO KAZUKO

Clinical significance of a positive Clostridioides difficile glutamate dehydrogenase test on the outcomes of hospitalized older patients.

Yohsuke Nagayoshi, Kazuko Yamamoto, Shuntaro Sato, Naofumi Suyama, Takuya Izumikawa, Kinichi Izumikawa, Taiga Miyazaki, Koichi Izumikawa, Katsunori Yanagihara, Hiroshi Mukae

Geriatrics & gerontology international ( Geriatrics and Gerontology International )  20 ( 12 ) 1138 - 1144   2020.10 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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AIM: Clostridioides difficile infection worsens the outcome of older hospitalized patients; thus, its diagnosis is necessary for the nosocomial infection control. The standard diagnostic test's limited sensitivity for Clostridioides difficile infection, an enzyme immunoassay for Clostridioides difficile toxins, is of clinical concern. Glutamate dehydrogenase detection is usually tested combined with Clostridioides difficile toxins. However, the clinical significance of a positive glutamate dehydrogenase result is unclear. We evaluated the association between positive glutamate dehydrogenase results, in-hospital mortality and hospital stay length among older patients with suspected Clostridioides difficile infection. METHODS: In this retrospective cohort study, we examined the data of patients who received antibiotics (except for Clostridioides difficile infection treatment) after admission and tested for Clostridioides difficile infection using an enzyme immunoassay for Clostridioides difficile toxins and glutamate dehydrogenase in a secondary care hospital located in a rural region with high aging rate, between 2015 and 2018. RESULTS: In total, 188 patients were included (83.5% of them aged >75 years). Glutamate dehydrogenase positivity was independently associated with in-hospital mortality (adjusted odds ratio 2.19, 95% confidence interval 1.14-4.21) and hospital stay length (regression coefficient 16.0, 95% confidence interval 5.15-26.9). Clostridioides difficile toxin positivity was independently associated with hospital stay duration (regression coefficient 14.5, 95% confidence interval 0.04-29.1), unlike in-hospital mortality. CONCLUSIONS: Glutamate dehydrogenase was closely related to in-hospital mortality and prolonged hospitalization compared with Clostridioides difficile toxin. Clinicians should not neglect glutamate dehydrogenase-positive patients, even when they are Clostridioides difficile toxin-negative, and consider them as having poor prognostic potential. Geriatr Gerontol Int 2020; ••: ••-••.

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Novel and potent antimicrobial effects of caspofungin on drug-resistant Candida and bacteria.

Makoto Sumiyoshi, Taiga Miyazaki, Juliann Nzembi Makau, Satoshi Mizuta, Yoshimasa Tanaka, Takeshi Ishikawa, Koichi Makimura, Tatsuro Hirayama, Takahiro Takazono, Tomomi Saijo, Hiroyuki Yamaguchi, Shintaro Shimamura, Kazuko Yamamoto, Yoshifumi Imamura, Noriho Sakamoto, Yasushi Obase, Koichi Izumikawa, Katsunori Yanagihara, Shigeru Kohno, Hiroshi Mukae

Scientific reports   10 ( 1 ) 17745 - 17745   2020.10 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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Echinocandins, including caspofungin, micafungin, and anidulafungin, are first-line antifungal agents for the treatment of invasive candidiasis. They exhibit fungicidal activity by inhibiting the synthesis of β-1,3-D-glucan, an essential component of the fungal cell wall. However, they are active only against proliferating fungal cells and unable to completely eradicate fungal cells even after a 24 h drug exposure in standard time-kill assays. Surprisingly, we found that caspofungin, when dissolved in low ionic solutions, had rapid and potent antimicrobial activities against multidrug-resistant (MDR) Candida and bacteria cells even in non-growth conditions. This effect was not observed in 0.9% NaCl or other ion-containing solutions and was not exerted by other echinocandins. Furthermore, caspofungin dissolved in low ionic solutions drastically reduced mature biofilm cells of MDR Candida auris in only 5 min, as well as Candida-bacterial polymicrobial biofilms in a catheter-lock therapy model. Caspofungin displayed ion concentration-dependent conformational changes and intracellular accumulation with increased reactive oxygen species production, indicating a novel mechanism of action in low ionic conditions. Importantly, caspofungin dissolved in 5% glucose water did not exhibit increased toxicity to human cells. This study facilitates the development of new therapeutic strategies in the management of catheter-related biofilm infections.

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An adult case of invasive pneumococcal disease due to serotype 12F-specific polysaccharide antibody failure following a 23-valent polysaccharide vaccination.

Yasuhiro Tanaka, Kazuko Yamamoto, Yuichi Fukuda, Asuka Umemura, Masataka Yoshida, Shuhei Ideguchi, Nobuyuki Ashizawa, Tatsuro Hirayama, Masato Tashiro, Takahiro Takazono, Yoshifumi Imamura, Taiga Miyazaki, Koichi Izumikawa, Katsunori Yanagihara, Bin Chang, Hiroshi Mukae

Emerging microbes & infections ( Emerging Microbes and Infections )  9 ( 1 ) 2266 - 2268   2020.10 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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A 68-year-old Japanese man was admitted to our hospital for an acute febrile illness with shivering and impaired consciousness. He was a previous smoker and had a history of chronic obstructive pulmonary disease, for which he inhaled steroid with a long-acting bronchodilator. He had received a 23-valent pneumococcal polysaccharide vaccination 2 years previously. He was intubated and placed on a ventilator in intensive care unit because of acute respiratory failure and hypercapnia. Streptococcus pneumoniae was grown from his blood, sputum, and urine cultures, and he was diagnosed with invasive pneumococcal disease with acute renal failure. He was treated with intravenous beta-lactam and macrolide with continuous hemodiafiltration and was discharged 3 months later. The pneumococcus was identified as serotype 12F, and his serotype-specific IgG and opsonophagocytic index against serotype 12F indicating a lack of protection from IPD among PPV23 serotypes. This case highlights that some individuals may have a serotype-specific polysaccharide antibody failure that makes them susceptible to serotype 12F invasive pneumococcal disease. This case also illustrates the need for serotype-specific IgG and opsonophagocytic index titre cut-offs for each specific pneumococcal serotype in available vaccines to understand the vaccination protection for individual patients better.

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Human immunodeficiency virus-associated vacuolar encephalomyelopathy with granulomatous-lymphocytic interstitial lung disease improved after antiretroviral therapy: a case report.

Kazumasa Akagi, Kazuko Yamamoto, Asuka Umemura, Shotaro Ide, Tatsuro Hirayama, Takahiro Takazono, Yoshifumi Imamura, Taiga Miyazaki, Noriho Sakamoto, Hirokazu Shiraishi, Hideaki Takahata, Yoshiaki Zaizen, Junya Fukuoka, Minoru Morikawa, Kazuto Ashizawa, Katsuji Teruya, Koichi Izumikawa, Hiroshi Mukae

AIDS research and therapy   17 ( 1 ) 38 - 38   2020.07 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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BACKGROUND: Vacuolar encephalomyelopathy, a disregarded diagnosis lately, was a major neurological disease in the terminal stages of human immunodeficiency virus (HIV)-1 infection in the pre-antiretroviral therapy (ART) era. Granulomatous-lymphocytic interstitial lung disease (GLILD) was classically identified as a non-infectious complication of common variable immunodeficiency; however, it is now being recognized in other immunodeficiency disorders. Here, we report the first case of GLILD accompanied by vacuolar encephalomyelopathy in a newly diagnosed HIV-infected man. CASE PRESENTATION: A 40-year-old Japanese man presented with chronic dry cough and progressing paraplegia. Radiological examination revealed diffuse pulmonary abnormalities in bilateral lungs, focal demyelinating lesions of the spinal cord, and white matter lesions in the brain. He was diagnosed with GLILD based on marked lymphocytosis detecting in bronchoalveolar lavage, and transbronchial-biopsy proven T-cellular interstitial lung disease with granulomas. Microbiological examinations did not reveal an etiologic agent. The patient was also diagnosed with HIV-associated vacuolar encephalomyelopathy on the basis of an elevated HIV viral load in cerebrospinal fluid. After initiating ART, the brain lesions and paraplegia improved significantly, and interstitial abnormalities of the lungs and cough disappeared. CONCLUSION: This report highlights that even in the post-ART era in developed countries with advanced healthcare services, HIV-associated vacuolar encephalomyelopathy should be considered in the differential diagnosis of a progressive neurological disorder during the first visit. Furthermore, GLILD may represent an HIV-associated pulmonary manifestation that can be treated by ART.

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Discrepancies in preferences regarding the care of terminal-phase pneumonia in elderly patients among patients, families, and doctors: A multicenter questionnaire survey in nagasaki, Japan.

Takahiro Takazono, Yoshifumi Imamura, Kaoru Kawakami, Naoya Yamasaki, Hiroyoshi Shimizu, Katsuhiro Usuki, Maiko Kiyohara, Tatsuro Hirayama, Masato Tashiro, Naoki Hosogaya, Tomomi Saijo, Kazuko Yamamoto, Taiga Miyazaki, Katsunori Yanagihara, Koichi Izumikawa, Hiroshi Mukae

Respiratory investigation   58 ( 6 ) 488 - 494   2020.07 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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BACKGROUND: Before advance care planning, it is essential to understand the differences in preferences for medical care of terminal-phase pneumonia in elderly patients among the patients, their families, and their doctors. This study aimed to clarify these differences and investigate the actual care provided to elderly patients with pneumonia in nursing hospitals. METHODS: Multicenter questionnaire surveys of 179 patients admitted to nursing homes and long-term care beds in hospitals of three healthcare corporations, their families, and their physicians were conducted between January and August 2018. The questionnaires mainly assessed preferences for life-prolonging medical care procedures, including antibiotic treatments, in terminal-phase pneumonia. A follow-up survey regarding the prognosis and the actual care provided by the physicians was conducted 1 year after the first survey. RESULTS: Only 16.2% of the patients had sufficient prior discussions with their families about their care. More families preferred cardiac massage, intubation, and tracheostomy, while fewer families preferred peripheral intravenous fluids or antibiotics than physicians. A total of 30 patients' families (16.7%) answered to withhold antibiotic treatment, while all physicians supported antibiotic administration. The only significant factor related to withholding antibiotics was high age (P = 0.0057). The follow-up survey administered to the doctors revealed that 49 patients (35.7%) had died within one year. Of the 137 patients, 54 patients (39.4%) had developed pneumonia during this observation period and all were treated with antibiotics. CONCLUSIONS: This study revealed large discrepancies between patients/families and physicians regarding preferences for care. Medical staff should make efforts to fill the gap by ensuring advance care planning.

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Roles of Elm1 in antifungal susceptibility and virulence in Candida glabrata.

Yuya Ito, Taiga Miyazaki, Yutaka Tanaka, Takashi Suematsu, Hironobu Nakayama, Akihiro Morita, Tatsuro Hirayama, Masato Tashiro, Takahiro Takazono, Tomomi Saijo, Shintaro Shimamura, Kazuko Yamamoto, Yoshifumi Imamura, Koichi Izumikawa, Katsunori Yanagihara, Shigeru Kohno, Hiroshi Mukae

Scientific reports   10 ( 1 ) 9789 - 9789   2020.06 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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Elm1 is a serine/threonine kinase involved in multiple cellular functions, including cytokinesis, morphogenesis, and drug resistance in Saccharomyces cerevisiae; however, its roles in pathogenic fungi have not been reported. In this study, we created ELM1-deletion, ELM1-reconstituted, ELM1-overexpression, and ELM1-kinase-dead strains in the clinically important fungal pathogen Candida glabrata and investigated the roles of Elm1 in cell morphology, stress response, and virulence. The elm1Δ strain showed elongated morphology and a thicker cell wall, with analyses of cell-wall components revealing that this strain exhibited significantly increased chitin content relative to that in the wild-type and ELM1-overexpression strains. Although the elm1Δ strain exhibited slower growth than the other two strains, as well as increased sensitivity to high temperature and cell-wall-damaging agents, it showed increased virulence in a Galleria mellonella-infection model. Moreover, loss of Elm1 resulted in increased adhesion to agar plates and epithelial cells, which represent important virulence factors in C. glabrata. Furthermore, RNA sequencing revealed that expression levels of 30 adhesion-like genes were elevated in the elm1Δ strain. Importantly, all these functions were mediated by the kinase activity of Elm1. To our knowledge, this is the first report describing the functional characterization of Elm1 in pathogenic fungi.

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A 71-Year-Old Man With Dyspnea and Cough During Chemotherapy

Kazuko Yamamoto, Koji Ando, Moe Tanaka, Hirokazu Yura, Noriho Sakamoto, Yoshiaki Zaizen, Kazuto Ashizawa, Junya Fukuoka, Yasushi Miyazaki, Hiroshi Mukae

Chest ( Elsevier BV )  157 ( 5 ) e165 - e171   2020.05 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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Evaluation of endobronchial volatile sulfur compounds for rapid diagnosis of lung abscesses caused by obligate anaerobes using Oral Chroma™: A pilot study.

Takahiro Takazono, Yoshifumi Imamura, Masayasu Kitamura, Reiko Furugen, Tatsuro Hirayama, Masato Tashiro, Tomomi Saijo, Kazuko Yamamoto, Taiga Miyazaki, Toshiyuki Saito, Koichi Izumikawa, Katsunori Yanagihara, Hiroshi Mukae

Respiratory investigation   58 ( 3 ) 212 - 215   2020.05 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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Endobronchial volatile sulfur compounds in patients with lung abscess or lung cancer were measured using the Oral Chroma™ gas chromatograph. High levels of hydrogen sulfide and methyl mercaptan were observed in some patients with lung abscess but not in patients with lung cancer. Measuring endobronchial volatile sulfur compounds could be useful for the rapid diagnosis of lung abscess caused by obligate anaerobes.

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Detection of viral RNA in diverse body fluids in an SFTS patient with encephalopathy, gastrointestinal bleeding and pneumonia: a case report and literature review.

Kazumasa Akagi, Taiga Miyazaki, Kazuhiro Oshima, Asuka Umemura, Satoshi Shimada, Kouichi Morita, Hiroaki Senju, Masato Tashiro, Takahiro Takazono, Tomomi Saijo, Shintaro Kurihara, Motohiro Sekino, Kazuko Yamamoto, Yoshifumi Imamura, Koichi Izumikawa, Katsunori Yanagihara, Akihiko Uda, Shigeru Morikawa, Tomoki Yoshikawa, Takeshi Kurosu, Masayuki Shimojima, Masayuki Saijo, Hiroshi Mukae

BMC infectious diseases   20 ( 1 ) 281 - 281   2020.04 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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BACKGROUND: Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease that commonly has a lethal course caused by the tick-borne Huaiyangshan banyang virus [former SFTS virus (SFTSV)]. The viral load in various body fluids in SFTS patients and the best infection control measure for SFTS patients have not been fully established. CASE PRESENTATION: A 79-year-old man was bitten by a tick while working in the bamboo grove in Nagasaki Prefecture in the southwest part of Japan. Due to the occurrence of impaired consciousness, he was referred to Nagasaki University Hospital for treatment. The serum sample tested positive for SFTSV-RNA in the genome amplification assay, and he was diagnosed with SFTS. Furthermore, SFTSV-RNA was detected from the tick that had bitten the patient. He was treated with multimodal therapy, including platelet transfusion, antimicrobials, antifungals, steroids, and continuous hemodiafiltration. His respiration was assisted with mechanical ventilation. On day 5, taking the day on which he was hospitalized as day 0, serum SFTSV-RNA levels reached a peak and then decreased. However, the cerebrospinal fluid collected on day 13 was positive for SFTSV-RNA. In addition, although serum SFTSV-RNA levels decreased below the detectable level on day 16, he was diagnosed with pneumonia with computed tomography. SFTSV-RNA was detected in the bronchoalveolar lavage fluid on day 21. By day 31, he recovered consciousness completely. The pneumonia improved by day 51, but SFTSV-RNA in the sputum remained positive for approximately 4 months after disease onset. Strict countermeasures against droplet/contact infection were continuously conducted. CONCLUSIONS: Even when SFTSV genome levels become undetectable in the serum of SFTS patients in the convalescent phase, the virus genome remains in body fluids and tissues. It may be possible that body fluids such as respiratory excretions become a source of infection to others; thus, careful infection control management is needed.

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Virulence assessment of six major pathogenic Candida species in the mouse model of invasive candidiasis caused by fungal translocation.

Tatsuro Hirayama, Taiga Miyazaki, Yuya Ito, Megumi Wakayama, Kazutoshi Shibuya, Kohei Yamashita, Takahiro Takazono, Tomomi Saijo, Shintaro Shimamura, Kazuko Yamamoto, Yoshifumi Imamura, Koichi Izumikawa, Katsunori Yanagihara, Shigeru Kohno, Hiroshi Mukae

Scientific reports   10 ( 1 ) 3814 - 3814   2020.03 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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Gastrointestinal colonization has been considered as the primary source of candidaemia; however, few established mouse models are available that mimic this infection route. We therefore developed a reproducible mouse model of invasive candidiasis initiated by fungal translocation and compared the virulence of six major pathogenic Candida species. The mice were fed a low-protein diet and then inoculated intragastrically with Candida cells. Oral antibiotics and cyclophosphamide were then administered to facilitate colonization and subsequent dissemination of Candida cells. Mice infected with Candida albicans and Candida tropicalis exhibited higher mortality than mice infected with the other four species. Among the less virulent species, stool titres of Candida glabrata and Candida parapsilosis were higher than those of Candida krusei and Candida guilliermondii. The fungal burdens of C. parapsilosis and C. krusei in the livers and kidneys were significantly greater than those of C. guilliermondii. Histopathologically, C. albicans demonstrated the highest pathogenicity to invade into gut mucosa and liver tissues causing marked necrosis. Overall, this model allowed analysis of the virulence traits of Candida strains in individual mice including colonization in the gut, penetration into intestinal mucosa, invasion into blood vessels, and the subsequent dissemination leading to lethal infections.

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Selection of Oral Antifungals for Initial Maintenance Therapy in Chronic Pulmonary Aspergillosis: A Longitudinal Analysis.

Masato Tashiro, Takahiro Takazono, Tomomi Saijo, Kazuko Yamamoto, Yoshifumi Imamura, Taiga Miyazaki, Hiroshi Kakeya, Tsunehiro Ando, Kenji Ogawa, Kazuma Kishi, Issei Tokimatsu, Yuta Hayashi, Satoru Fujiuchi, Katsunori Yanagihara, Yoshitsugu Miyazaki, Kiyoshi Ichihara, Hiroshi Mukae, Shigeru Kohno, Koichi Izumikawa

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America   70 ( 5 ) 835 - 842   2020.02 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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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.

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Design and Synthesis of a Class of Compounds That Inhibit the Growth of Fungi Which Cause Invasive Infections

Nana Nakada-Motokawa, Taiga Miyazaki, Satoshi Mizuta, Yoshimasa Tanaka, Tatsuro Hirayama, Takahiro Takazono, Tomomi Saijo, Kazuko Yamamoto, Yoshifumi Imamura, Koichi Izumikawa, Katsunori Yanagihara, Koichi Makimura, Kohsuke Takeda, Shigeru Kohno, Hiroshi Mukae

ChemistrySelect   5 ( 3 ) 1140 - 1145   2020.01 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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© 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Invasive fungal infections are growing causes of morbidity and mortality in immunocompromised patients. However, only one antifungal drug class has been developed in the last 30 years, extremely limiting current therapeutic options. To address unmet medical needs, we performed high-throughput screening of 9600 chemical compounds and identified an aminohydrazone derivative as a novel and potent antifungal compound. We then designed and synthesized a series of aminohydrazone derivatives, and demonstrated that 1-[(E)-[4-(3′,4′-dichlorobenxyloxy)phenyl methylidene]amino]-guanidine had the most potent inhibitory activity and exhibited a broad spectrum of antifungal activities against Candida species (including multidrug resistant C. auris), Aspergillus species, Cryptococcus neoformans, and Rhizopus oryzae. Against C. albicans, the leading cause of Candida infections, the compound had fungicidal activity for planktonic cells at 8 μg mL−1 (25 μM) and anti-biofilm activity at 34 μg mL−1 (100 μM). This study provides new insights for the development of a new drug class for the treatment of invasive fungal infections which are often refractory to conventional therapies.

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Detection of invasive pulmonary aspergillosis in mice using lung perfusion single-photon emission computed tomography with [99mTc]MAA.

Masataka Yoshida, Masato Tashiro, Kodai Nishi, Maki Mishima, Kei Kawano, Takahiro Takazono, Tomomi Saijo, Kazuko Yamamoto, Yoshifumi Imamura, Taiga Miyazaki, Takashi Kudo, Katsunori Yanagihara, Hiroshi Mukae, Koichi Izumikawa

Medical mycology   58 ( 7 ) 965 - 972   2020.01 [ Peer Review Accepted ]

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There is an urgent need for development of better diagnostic strategies to improve outcomes in patients with invasive pulmonary aspergillosis (IPA). We hypothesized that lung perfusion single-photon emission computed tomography (SPECT) may be more sensitive and specific than computed tomography (CT) of the chest for detection of IPA because it is an angioinvasive pulmonary infection with characteristics that are different from those of bacterial pneumonia. We used SPECT with injection of technetium-99m-labeled macroaggregated albumin ([99mTc]MAA) to measure pulmonary perfusion in noninfected mice, mice with IPA, and mice with bacterial pneumonia. Histopathologic analysis was performed to evaluate the correlation between the perfusion defect and mould invasion. We also attempted to quantitatively evaluate the SPECT images to identify differences in decreased perfusion levels in affected areas in the mouse lung. Histopathologic analysis in the IPA mouse model showed a clear match between areas with a perfusion defect and the presence of mold, indicating that the location of the perfusion defect on a SPECT image reflects angioinvasion of the mould in the lungs. Some of these perfusion defects could be seen before appearance of the infiltrate of CT images. Quantitative analysis confirmed that perfusion in the affected areas was significantly decreased in the IPA model but not in the bacterial pneumonia model (P < .0001). This imaging method may be preferable to the alternative methods presently used to identify the presence of mold in a patient's lungs.

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Epithelial membrane protein 2 governs transepithelial migration of neutrophils into the airspace

Wan-Chi Lin, Kymberly M. Gowdy, Jennifer H. Madenspacher, Rachel L. Zemans, Kazuko Yamamoto, Miranda Lyons-Cohen, Hideki Nakano, Kyathanahalli Janardhan, Carmen J. Williams, Donald N. Cook, Joseph P. Mizgerd, Michael B. Fessler

Journal of Clinical Investigation ( American Society for Clinical Investigation )  130 ( 1 ) 157 - 170   2020.01 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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Severe Fever with Thrombocytopenia Syndrome Virus RNA in Semen, Japan.

Satoru Koga, Takahiro Takazono, Tsuyoshi Ando, Daisuke Hayasaka, Masato Tashiro, Tomomi Saijo, Shintaro Kurihara, Motohiro Sekino, Kazuko Yamamoto, Yoshifumi Imamura, Taiga Miyazaki, Katsunori Yanagihara, Kouichi Morita, Koichi Izumikawa, Hiroshi Mukae

Emerging infectious diseases   25 ( 11 ) 2127 - 2128   2019.11 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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Severe fever with thrombocytopenia syndrome virus (SFTSV) can be transmitted between humans. We describe a case of severe fever with thrombocytopenia syndrome in which SFTSV RNA was detected in semen after its disappearance from serum. Our findings indicate possible sexual transmission of this emerging virus.

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The efficacy and safety of sitafloxacin and garenoxacin for the treatment of pneumonia in elderly patients: A randomized, multicenter, open-label trial.

Taiga Miyazaki, Shigeki Nakamura, Kohji Hashiguchi, Tsutomu Kobayashi, Kiyoyasu Fukushima, Yuichi Fukuda, Akira Kondo, Yuichi Inoue, Hironobu Koga, Eisuke Sasaki, Yosuke Nagayoshi, Yasuhito Higashiyama, Masataka Yoshida, Takahiro Takazono, Tomomi Saijo, Yoshitomo Morinaga, Kazuko Yamamoto, Yoshifumi Imamura, Shinya Mikushi, Koichi Izumikawa, Katsunori Yanagihara, Shigeru Kohno, Hiroshi Mukae

Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy   25 ( 11 ) 886 - 893   2019.11 [ Peer Review Accepted ]

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Oral treatment for elderly outpatients with pneumonia is becoming increasingly important in this super-aged society from the perspective of cost-effectiveness and limited hospital capacities. We evaluated the efficacy and safety of two oral respiratory quinolones, sitafloxacin and garenoxacin, in elderly patients with pneumonia. This randomized, multicenter, open-label trial was conducted among patients aged ≥65 years with clinically and radiographically confirmed pneumonia in Japan. Patients were randomly assigned (1:1) to receive either sitafloxacin (100 mg/day) or garenoxacin (400 mg/day) for 3-10 days. The primary efficacy endpoint was the clinical cure rate at 5-10 days after the end of treatment. From December 2013 to November 2017, we enrolled 120 patients at 11 hospitals and randomly assigned 59 patients to the sitafloxacin group (1 patient withdrew) and 61 patients to the garenoxacin group. These included 30 patients with nursing and healthcare-associated pneumonia (NHCAP) (18 receiving sitafloxacin, 12 receiving garenoxacin) and 37 patients with aspiration pneumonia (16 receiving sitafloxacin, 21 receiving garenoxacin). The clinical cure rates in the sitafloxacin and garenoxacin groups were 88.5% (95% confidence interval: 76.6-95.6) and 88.9% (95% confidence interval: 77.4-95.8), respectively. No significant differences were observed in the incidence rates of drug-related adverse events between the sitafloxacin (20.7%; 12/58 patients) and garenoxacin (27.9%; 17/61 patients) groups. The most common adverse event was hepatic dysfunction, which occurred in seven patients in each group. We conclude that sitafloxacin and garenoxacin are comparably effective and safe for the treatment of pneumonia, including NHCAP and aspiration pneumonia, in elderly patients.

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Efficacy and safety of cefditoren pivoxil for exacerbations of chronic obstructive pulmonary disease: A prospective multicenter interventional study.

Taiga Miyazaki, Kiyoyasu Fukushima, Kohji Hashiguchi, Yuichi Inoue, Tomo Mihara, Toyomitsu Sawai, Naofumi Suyama, Tsutomu Kobayashi, Akira Kondo, Yuichi Fukuda, Yosuke Harada, Eisuke Sasaki, Norihito Kaku, Shotaro Ide, Takahiro Takazono, Tomomi Saijo, Kosuke Kosai, Yoshitomo Morinaga, Shigeki Nakamura, Kazuko Yamamoto, Yoshifumi Imamura, Koichi Izumikawa, Katsunori Yanagihara, Shigeru Kohno, Hiroshi Mukae

Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy   25 ( 9 ) 702 - 707   2019.09 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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Oral antibiotic therapy for patients with acute exacerbations of chronic obstructive pulmonary disease (COPD) usually involves an aminopenicillin with clavulanic acid, a macrolide, or a quinolone. To date, however, the clinical efficacy and safety of the oral cephalosporin cefditoren pivoxil has not been evaluated in Japanese patients with acute exacerbations of COPD. We conducted a prospective, multicenter, single arm, interventional study from January 2013 to March 2017 to determine the efficacy and safety of oral administration of 200 mg cefditoren pivoxil three times daily for 7 days in a cohort of 29 eligible patients from 15 hospitals. The mean age (SD) of participants was 73.1 (8.1) years and 28 had a smoking history (the mean [SD] of smoking index, 1426.7 [931.7]). The primary efficacy endpoint was clinical response (cure rate) at test of cure, which was set at 5-10 days after treatment ceased. Of the 23 patients finally analyzed, cure was achieved in 15 (65.2%), while 8 (34.8%) remained uncured. Previous experience of acute exacerbations significantly affected the cure rate: none of the three patients who had at least two prior exacerbations were cured, while 15 of the 20 patients with one or fewer prior exacerbations were cured (p = 0.032). The microbiological eradication rate was 88.9% at test of cure. During treatment, mild pneumonia was reported as an adverse event in one patient (3.4%) but resolved within 10 days of onset. We conclude that cefditoren pivoxil represents a viable alternative for antibiotic therapy in patients with few prior exacerbations.

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Munchausen syndrome mimicking refractory subcutaneous abscess with bacteremia, diagnosed by repetitive element sequence-based polymerase chain reaction: a case report.

Iwanaga N, Yamamoto K, Takazono T, Saijo T, Imamura Y, Miyazaki T, Izumikawa K, Yamamoto Y, Yanagihara K, Yasuoka A, Mukae H

Journal of medical case reports   13 ( 1 ) 287 - 287   2019.09 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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BACKGROUND: Rapid diagnosis and appropriate treatment of Munchausen syndrome is important not only for the patient but also for health care workers because a delay in diagnosis can worsen patients' clinical outcomes, and result in a substantial medical cost. CASE PRESENTATION: A young and previously healthy 24-year-old Japanese woman, a nurse, presented with complaints of refractory abscess on her left upper limb for 3 months. A physical examination on admission revealed low-grade fever and a subcutaneous abscess in her left forearm. Laboratory data suggested mild systemic inflammation and liver dysfunction, but no abnormalities of the immune system, including changes in the number of lymphocytes and neutrophils, neutrophil phagocytic capacity, and natural killer (NK) cell activity, were observed. A human immunodeficiency virus test was also negative. Multiple modalities, including positron emission tomography-computed tomography, failed to detect any cause and focus of infection except her left upper limb. Streptococcus mitis and Prevotella buccae were detected from the wound, but no microorganisms were detected in a blood culture. The cellulitis promptly resolved; however, exacerbation of the subcutaneous abscess with polymicrobial bacteremia repeatedly occurred unexpectedly. Because of this puzzling clinical course, the possibility of self-injury was finally suspected. Three syringes with needles, with a turbid liquid, were found in our patient's bag. Enterobacter cloacae and Enterococcus faecalis were detected in the liquid, and an analysis via repetitive element sequence-based polymerase chain reaction determined that Enterococcus faecalis in the wound and syringe contents were genetically identical. She was diagnosed as having Munchausen syndrome and treated with the collaboration of a psychiatrist. She finally confessed that she had injected her own saliva and toilet water into the drip line and wound. CONCLUSIONS: This case report is valuable in that it is the first case in which this syndrome was diagnosed by a genetic method. Munchausen syndrome should not be neglected as a possible cause of refractory and recurrent infection.

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The Novel Arylamidine T-2307 Selectively Disrupts Yeast Mitochondrial Function by Inhibiting Respiratory Chain Complexes.

Kohei Yamashita, Taiga Miyazaki, Yoshiko Fukuda, Junichi Mitsuyama, Tomomi Saijo, Shintaro Shimamura, Kazuko Yamamoto, Yoshifumi Imamura, Koichi Izumikawa, Katsunori Yanagihara, Shigeru Kohno, Hiroshi Mukae

Antimicrobial agents and chemotherapy   63 ( 8 )   2019.08 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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The novel arylamidine T-2307 exhibits broad-spectrum in vitro and in vivo antifungal activities against clinically significant pathogens. Previous studies have shown that T-2307 accumulates in yeast cells via a specific polyamine transporter and disrupts yeast mitochondrial membrane potential. Further, it has little effect on rat liver mitochondrial function. The mechanism by which T-2307 disrupts yeast mitochondrial function is poorly understood, and its elucidation may provide important information for developing novel antifungal agents. This study aimed to determine how T-2307 promotes yeast mitochondrial dysfunction and to investigate the selectivity of this mechanism between fungi and mammals. T-2307 inhibited the respiration of yeast whole cells and isolated yeast mitochondria in a dose-dependent manner. The similarity of the effects of T-2307 and respiratory chain inhibitors on mitochondrial respiration prompted us to investigate the effect of T-2307 on mitochondrial respiratory chain complexes. T-2307 particularly inhibited respiratory chain complexes III and IV not only in Saccharomyces cerevisiae but also in Candida albicans, indicating that T-2307 acts against pathogenic fungi in a manner similar to that of yeast. Conversely, T-2307 showed little effect on bovine respiratory chain complexes. Additionally, we demonstrated that the inhibition of respiratory chain complexes by T-2307 resulted in a decrease in the intracellular ATP levels in yeast cells. These results indicate that inhibition of respiratory chain complexes III and IV is a key factor for selective disruption of yeast mitochondrial function and antifungal activity.

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Evaluation of Candida peritonitis with underlying peritoneal fibrosis and efficacy of micafungin in murine models of intra-abdominal candidiasis.

Nobuyuki Ashizawa, Taiga Miyazaki, Shinichi Abe, Takahiro Takazono, Tomomi Saijo, Yoko Obata, Shintaro Shimamura, Kazuko Yamamoto, Yoshifumi Imamura, Takehiko Koji, Tomoya Nishino, Koichi Izumikawa, Katsunori Yanagihara, Shigeru Kohno, Hiroshi Mukae

Scientific reports   9 ( 1 ) 9331 - 9331   2019.06 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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Candida peritonitis is a crucial disease, however the optimal antifungal therapy regimen has not been clearly defined. Peritoneal fibrosis (PF) can be caused by abdominal surgery, intra-abdominal infection, and malignant diseases, and is also widely recognized as a crucial complication of long-term peritoneal dialysis. However, the influence of PF on Candida peritonitis prognosis remains unknown. Here, we evaluated the severity of Candida peritonitis within the context of PF and the efficacy of micafungin using mice. A PF mouse model was generated by intraperitoneally administering chlorhexidine gluconate. Candida peritonitis, induced by intraperitoneal inoculation of Candida albicans, was treated with a 7-day consecutive subcutaneous administration of micafungin. Candida infection caused a higher mortality rate in the PF mice compared with the control mice on day 7. Proliferative Candida invasion into the peritoneum and intra-abdominal organs was confirmed pathologically only in the PF mice. However, all mice in both groups treated with micafungin survived until day 20. Micafungin treatment tends to suppress inflammatory cytokines in the plasma 12 h after infection in both groups. Our results suggest that PF enhances early mortality in Candida peritonitis. Prompt initiation and sufficient doses of micafungin had good efficacy for Candida peritonitis, irrespective of the underlying PF.

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