Published Papers - YAMAMOTO KAZUKO

Evaluation of <i>Aspergillus</i>-Specific Lateral-Flow Device Test Using Serum and Bronchoalveolar Lavage Fluid for Diagnosis of Chronic Pulmonary Aspergillosis.

Takazono T, Ito Y, Tashiro M, Nishimura K, Saijo T, Yamamoto K, Imamura Y, Miyazaki T, Yanagihara K, Mukae H, Izumikawa K

Journal of clinical microbiology   57 ( 5 )   2019.05 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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The Aspergillus-specific lateral-flow device (AspLFD) test is a newly developed point-of-care diagnostic method for invasive pulmonary aspergillosis. However, evidence of the diagnostic performance of the AspLFD for chronic pulmonary aspergillosis (CPA) is limited. Therefore, we conducted a retrospective study to investigate this in comparison with the galactomannan (GM) β-d-glucan (BDG) test. Fifty patients with chronic pulmonary aspergillosis and 65 patients with respiratory disease, as a control, were enrolled in this study. The majority of the CPA disease entities were chronic pulmonary aspergillosis (64.0%, n = 32), followed by subacute invasive pulmonary aspergillosis (IPA) (20.0%, n = 10) and simple pulmonary aspergilloma (SPA) (16.0%, n = 8). The sensitivity and specificity of the AspLFD test in serum samples were 62.0% and 67.7%, respectively. The GM test (cutoff index, 1.54) showed a sensitivity of 22% and a specificity of 92.3%, while the sensitivity and specificity of the BDG test (cutoff, 19.3 pg/ml) were 48% and 90.8%, respectively. In bronchoalveolar lavage fluid samples, the AspLFD test showed a sensitivity of 66.7% and a specificity of 69.2%, while those of the GM test (cutoff index, 0.6) were 72.7% and 83.1%, respectively. The Aspergillus precipitating antibody test had 70% sensitivity. Unlike the Aspergillus precipitating antibody test, the AspLFD on serum samples showed similar sensitivity to non-fumigatus Aspergillus species. Patients with false-positive results for the AspLFD on serum samples were of a significantly higher age and had a higher prevalence of cavitary lesions in chest computed tomography than patients with negative results in the control group. Given the results in this study, the performance of the AspLFD using serum was acceptable as a point-of-care test for the diagnosis of CPA.

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A case of bilateral emphysematous pyelonephritis caused by Candida albicans.

Ideguchi S, Yamamoto K, Ikeda A, Hashimoto K, Takazono T, Saijo T, Imamura Y, Miyazaki T, Mukae H

Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy ( Journal of Infection and Chemotherapy )  25 ( 4 ) 302 - 306   2019.04 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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Emphysematous pyelonephritis (EPN) is a life-threatening renal infection characterized by the formation of gas within the renal parenchyma and collecting duct system, as well as perinephric tissues. We herein report a case of bilateral EPN accompanied by the urinary tract infection caused by spherical growth of Candida albicans in a patient with underlying diabetes mellitus and prostate cancer. The diagnosis was assisted by computed tomography, urography, and gram staining. Despite immediate percutaneous catheter drainage and a 4-week course of antifungal treatment, the C. albicans infection was refractory, as indicated by continuous isolation from the urine, and the patient eventually died. A local autopsy of urinary organs revealed C. albicans in the renal tissue. EPN caused by Candida species frequently occurs in men, and almost all cases have underlying poorly controlled diabetes. This condition is subject to delayed diagnosis, which may lead to extended disease and high mortality. Candida species should be considered as causative microorganism for refractory EPN in patients with poorly controlled diabetes who are receiving antibiotic treatment. Gram staining may contribute to an early diagnosis of EPN caused by Candida species, which may require long-term antifungal therapy.

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Clinical features and cause analysis of false positive results of Aspergillus galactomannan assay in pulmonary cryptococcosis patients.

Takazono T, Saijo T, Ashizawa N, Oshima K, Nishimura K, Tashiro M, Yamamoto K, Imamura Y, Miyazaki T, Yanagihara K, Mukae H, Izumikawa K, Sheppard DC

European journal of clinical microbiology & infectious diseases : official publication of the European Society of Clinical Microbiology ( European Journal of Clinical Microbiology and Infectious Diseases )  38 ( 4 ) 735 - 741   2019.04 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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There have been conflicting reports of false positive galactomannan assay results in patients with systemic cryptococcosis. We sought to determine the frequency of GM positivity in patients with pulmonary cryptococcosis and confirm the source of this cross-reactivity in vitro. We conducted a retrospective study to elucidate the rate of galactomannan (GM) false positivity and cause in a cohort of 29 patients with pulmonary cryptococcal disease. The production of GM cross-reacting substances by clinical isolates and laboratory isolates of C. neoformans was tested in vitro. The mean serum GM index (Platelia Aspergillus) in patients with pulmonary cryptococcosis was 1.06, with 16 (55.2%) of patients having values above the positive cutoff value of 0.5. GM index values significantly decreased after treatment of cryptococcosis. There was no significant correlation between galactomannan and cryptococcal glucuronoxylomannan antigen (Eiken Latex test) results. Culture supernatants from clinical isolates and wild-type C. neoformans did not react in the GM assay; however, growth in the presence of 6% sodium chloride induced the production of cross-reacting GM antigens in culture supernatants from clinical isolates, wild type and a glucuronoxylomannan-deficient mutant of C. neoformans, but not in culture supernatants from a galactoxylomannan-deficient strain. Our results support the cross-reactivity of cryptococcal galactoxylomannan with the serum GM assay in vitro and in patients with pulmonary cryptococcal infection.

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Autophagy-Inducing Factor Atg1 Is Required for Virulence in the Pathogenic Fungus Candida glabrata.

Shintaro Shimamura, Taiga Miyazaki, Masato Tashiro, Takahiro Takazono, Tomomi Saijo, Kazuko Yamamoto, Yoshifumi Imamura, Koichi Izumikawa, Katsunori Yanagihara, Shigeru Kohno, Hiroshi Mukae

Frontiers in microbiology ( Frontiers in Microbiology )  10 ( JAN ) 27 - 27   2019 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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Candida glabrata is one of the leading causes of candidiasis and serious invasive infections in hosts with weakened immune systems. C. glabrata is a haploid budding yeast that resides in healthy hosts. Little is known about the mechanisms of C. glabrata virulence. Autophagy is a 'self-eating' process developed in eukaryotes to recycle molecules for adaptation to various environments. Autophagy is speculated to play a role in pathogen virulence by supplying sources of essential proteins for survival in severe host environments. Here, we investigated the effects of defective autophagy on C. glabrata virulence. Autophagy was induced by nitrogen starvation and hydrogen peroxide (H2O2) in C. glabrata. A mutant strain lacking CgAtg1, an autophagy-inducing factor, was generated and confirmed to be deficient for autophagy. The Cgatg1Δ strain was sensitive to nitrogen starvation and H2O2, died rapidly in water without any nutrients, and showed high intracellular ROS levels compared with the wild-type strain and the CgATG1-reconstituted strain in vitro. Upon infecting mouse peritoneal macrophages, the Cgatg1Δ strain showed higher mortality from phagocytosis by macrophages. Finally, in vivo experiments were performed using two mouse models of disseminated candidiasis and intra-abdominal candidiasis. The Cgatg1Δ strain showed significantly decreased CFUs in the organs of the two mouse models. These results suggest that autophagy contributes to C. glabrata virulence by conferring resistance to unstable nutrient environments and immune defense of hosts, and that Atg1 is a novel fitness factor in Candida species.

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[Ectopic pulmonary calcification after parathyroidectomy in multiple myeloma].

Koji Ando, Yoshitaka Imaizumi, Kazuko Yamamoto, Moe Tanaka, Yoshiaki Zaizen, Masataka Taguchi, Chika Sakaki, Masahiro Ichinose, Takafumi Furumoto, Miki Hashimoto, Machiko Fujioka, Hikaru Sakamoto, Makiko Hourai, Hidehiro Itonaga, Shinya Sato, Yasushi Sawayama, Tomoko Hata, Hiroshi Mukae, Junya Fukuoka, Daisuke Inoue, Yasushi Miyazaki

[Rinsho ketsueki] The Japanese journal of clinical hematology   60 ( 7 ) 785 - 790   2019 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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Ectopic soft tissue calcification (ESTC), a rare clinical condition, causes tissue and organ damage. It is associated with chronic renal failure, hyperparathyroidism, and malignant neoplasms, including multiple myeloma, and it is reportedly resistant to treatment. Here, we present the case of a 71-year-old male with multiple myeloma who had rapid ESTC in the lung. He had developed hypoparathyroidism secondary to thyroidectomy. During the course of our observation, he rapidly developed ectopic pulmonary calcification approximately 2 weeks after acquiring an infection. There was no evidence of further progression of multiple myeloma after the onset of ESTC, and treatment with ferric citrate hydrate and precipitated calcium resulted in immediate improvement of his pulmonary signs. We recommend cautious monitoring for patients with multiple myeloma and hypoparathyroidism to detect the onset of ectopic calcification. In addition, low blood phosphorus levels should be effectively treated.

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Vacuolar proton-translocating ATPase is required for antifungal resistance and virulence of Candida glabrata.

Asuka Minematsu, Taiga Miyazaki, Shintaro Shimamura, Hiroshi Nishikawa, Hironobu Nakayama, Takahiro Takazono, Tomomi Saijo, Kazuko Yamamoto, Yoshifumi Imamura, Katsunori Yanagihara, Shigeru Kohno, Hiroshi Mukae, Koichi Izumikawa

PloS one   14 ( 1 ) e0210883   2019 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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Vacuolar proton-translocating ATPase (V-ATPase) is located in fungal vacuolar membranes. It is involved in multiple cellular processes, including the maintenance of intracellular ion homeostasis by maintaining acidic pH within the cell. The importance of V-ATPase in virulence has been demonstrated in several pathogenic fungi, including Candida albicans. However, it remains to be determined in the clinically important fungal pathogen Candida glabrata. Increasing multidrug resistance of C. glabrata is becoming a critical issue in the clinical setting. In the current study, we demonstrated that the plecomacrolide V-ATPase inhibitor bafilomycin B1 exerts a synergistic effect with azole antifungal agents, including fluconazole and voriconazole, against a C. glabrata wild-type strain. Furthermore, the deletion of the VPH2 gene encoding an assembly factor of V-ATPase was sufficient to interfere with V-ATPase function in C. glabrata, resulting in impaired pH homeostasis in the vacuole and increased sensitivity to a variety of environmental stresses, such as alkaline conditions (pH 7.4), ion stress (Na+, Ca2+, Mn2+, and Zn2+ stress), exposure to the calcineurin inhibitor FK506 and antifungal agents (azoles and amphotericin B), and iron limitation. In addition, virulence of C. glabrata Δvph2 mutant in a mouse model of disseminated candidiasis was reduced in comparison with that of the wild-type and VPH2-reconstituted strains. These findings support the notion that V-ATPase is a potential attractive target for the development of effective antifungal strategies.

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Clinical and Microbiological Characteristics of Candida guilliermondii and Candida fermentati.

Tatsuro Hirayama, Taiga Miyazaki, Yuka Yamagishi, Hiroshige Mikamo, Takashi Ueda, Kazuhiko Nakajima, Yoshio Takesue, Yoshitsugu Higashi, Yoshihiro Yamamoto, Muneyoshi Kimura, Hideki Araoka, Shuichi Taniguchi, Yuichi Fukuda, Yumi Matsuo, Akiko Furutani, Kohei Yamashita, Takahiro Takazono, Tomomi Saijo, Shintaro Shimamura, Kazuko Yamamoto, Yoshifumi Imamura, Koichi Izumikawa, Katsunori Yanagihara, Shigeru Kohno, Hiroshi Mukae

Antimicrobial agents and chemotherapy ( Antimicrobial Agents and Chemotherapy )  62 ( 6 )   2018.06 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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A total of 46 clinical isolates of Candida guilliermondii and Candida famata were reidentified genetically, resulting in 27 C. guilliermondii and 12 Candida fermentati strains. The majority of C. guilliermondii strains, but not C. fermentati strains, were isolated from blood cultures. C. fermentati was more sensitive to antifungals, hydrogen peroxide, and killing by murine macrophages than was C. guilliermondii The C. guilliermondii isolates were echinocandin susceptible in vitro but resistant to micafungin in a murine model of invasive candidiasis.

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Examination of cryptococcal glucuronoxylomannan antigen in bronchoalveolar lavage fluid for diagnosing pulmonary cryptococcosis in HIV-negative patients.

Kazuhiro Oshima, Takahiro Takazono, Tomomi Saijo, Masato Tashiro, Shintaro Kurihara, Kazuko Yamamoto, Yoshifumi Imamura, Taiga Miyazaki, Misuzu Tsukamoto, Katsunori Yanagihara, Hiroshi Mukae, Shigeru Kohno, Koichi Izumikawa

Medical mycology   56 ( 1 ) 88 - 94   2018.01 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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We clarified the performance of a cryptococcal glucuronoxylomannan (GXM) antigen test using bronchoalveolar lavage fluid (BALF) samples, in an HIV-negative Japanese population. Between March 2008 and December 2014, we examined cryptococcal GXM antigens in both serum and BALF specimens from 429 cases at Nagasaki University hospital. The diagnoses, underlying diseases, chest computed tomography findings, and cryptococcal GXM antigen test results were retrospectively investigated. Twenty-three patients were confirmed to have pulmonary cryptococcosis, another six were clinically diagnosed with cryptococcosis because they were seropositive for the GXM antigen, and five possible cryptococcosis cases had BALF samples that were positive for the GXM antigen and serum samples that were negative. The test's sensitivities for detecting cryptococcal GXM antigens in serum and BALF samples, for confirmed cases, were 73.9% and 82.6%, respectively, and their respective specificities were 98.5% and 97.8%. Three of the five putative patients with cryptococcosis were treated with antifungal agents; the pulmonary lesions decreased in size in all treated patients. Both the BALF and serum GXM antigen titers showed positive correlations with the lesion sizes; however, the serum antigen titers showed a higher correlation (r = 0.490, P = .0033) than did the BALF titres (r = 0.312, P = .0724). The rate of GXM-positive BALF samples was higher than the rate for serum samples, especially for patients with pulmonary lesion diameters ≤25 mm. Testing for the presence of the cryptococcal GXM antigen in BALF specimens might contribute to the early diagnosis of pulmonary cryptococcosis.

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Regionally compartmentalized resident memory T cells mediate naturally acquired protection against pneumococcal pneumonia.

Smith NMS, WassermanGA, Coleman FT, Hilliard KL, Yamamoto K, Lipsitz E, Malley R, Dooms H, Jones MR, Quinton LJ, Mizgerd JP

Mucosal Immunology   11 ( 1 ) 220 - 235   2018.01 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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Comparison of Efficacy of Antimicrobial Agents among Hospitalized Patients with Mycoplasma pneumoniae Pneumonia in Japan during Large Epidemics of Macrolide-Resistant M. pneumoniae Infections: A Nationwide Observational Study

Masato Tashiro, Kiyohide Fushimi, Kei Kawano, Takahiro Takazono, Tomomi Saijo, Kazuko Yamamoto, Shintaro Kurihara, Yoshifumi Imamura, Taiga Miyazaki, Katsunori Yanagihara, Hiroshi Mukae, Koichi Izumikawa

Clinical Infectious Diseases ( Oxford University Press )  65 ( 11 ) 1837 - 1842   2017.12 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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Background Mycoplasma pneumoniae strains with resistance to macrolides have been spreading worldwide. Here, we aimed to clarify which antimicrobial agent is a better treatment for patients with M. pneumoniae pneumonia in a setting with large epidemics of macrolide resistance. Methods Adult patients hospitalized with laboratory-confirmed M. pneumoniae pneumonia from 2010 to 2013 were identified from the Japanese Diagnosis Procedure Combination national database. Drug switching, length of stay (LOS), 30-day mortality, and total costs for patients who underwent macrolide, quinolone, and tetracycline therapy were compared using propensity score analyses. Results Eligible patients (N = 1650) from 602 hospitals were divided into the macrolide group (n = 508), quinolone group (n = 569), or tetracycline group (n = 573). We found that 52.8%, 21.8%, and 38.6% of patients in the macrolide, quinolone, and tetracycline groups, respectively, had to switch drugs (P &lt .0001). There was no significant difference in the LOS and the 30-day mortality rates among these 3 groups. Cost was highest in the quinolone group (P =.0062). The propensity score-matched pairs (n = 487×2) generated from the quinolone and tetracycline groups also showed a lower proportion of patients who require switches in the quinolone group than in the tetracycline group (21.2% vs 39.6%, P &lt .0001) but not in the LOS, mortality, and cost. Conclusions There were no significant differences in the LOS and mortality among any antimycoplasmal drugs as initial treatment for hospitalized M. pneumoniae pneumonia patients despite the lower switching rate in the quinolone group.

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Adjunctive corticosteroid therapy for inpatients with &ITMycoplasma pneumoniae&IT pneumonia

Masato Tashiro, Kiyohide Fushimi, Kei Kawano, Takahiro Takazono, Tomomi Saijo, Kazuko Yamamoto, Shintaro Kurihara, Yoshifumi Imamura, Taiga Miyazaki, Katsunori Yanagihara, Hiroshi Mukae, Koichi Izumikawa

BMC PULMONARY MEDICINE ( BIOMED CENTRAL LTD )  17 ( 1 ) 219   2017.12 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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Background: There is conflicting evidence regarding the benefit of adjunctive corticosteroid therapy in patients with Mycoplasma pneumoniae pneumonia. We hypothesised that corticosteroid therapy could reduce mortality and length of stay (LOS) in such patients.& para;& para;Methods: Adult patients with M. pneumoniae pneumonia from January 2010 to December 2013 were identified from the Japanese Diagnosis Procedure Combination inpatient database. The effects of low-dose and high-dose corticosteroid therapies on mortality, LOS, drug costs and hyperglycaemia requiring insulin treatment were evaluated using propensity score analyses.& para;& para;Results: Eligible patients (n = 2228) from 630 hospitals were divided into no-corticosteroid (n = 1829), low-dose corticosteroid (n = 267) and high-dose corticosteroid (n = 132) groups. The propensity score-matched pairs were generated from no-corticoid and low-dose corticoid groups (251 pairs), or no-corticoid and high-dose corticosteroid groups (120 pairs). Adjunctive corticosteroid therapy did not decrease 30-day mortality. In addition, both low-dose and high-dose corticosteroid therapies were associated with increases in LOS. Furthermore, hyperglycaemia requiring insulin treatment and drug cost increased with corticosteroid use. & para;& para;Conclusions: Adjunctive treatment with low-dose or high-dose corticosteroids may not be beneficial in M. pneumoniae pneumonia.

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Proposal of a new scoring system to predict prognosis of candidemia patients

Akagi K, Motokawa N, Miyazaki T, Saijo T, Yamamoto K, Imamura Y, Izumikawa K, Yanagihara K, Kohno S, Mukae H

International Journal of Antimicrobial Agents   50   S32   2017.11 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

Expression of Piwi protein MIWI2 defines a distinct population of multiciliated cells

Gregory A. Wasserman, Aleksander D. Szymaniak, Anne C. Hinds, Kazuko Yamamoto, Hirofumi Kamata, Nicole M. S. Smith, Kristie L. Hilliard, Claudia Carrieri, Adam T. Labadorf, Lee J. Quinton, Xingbin Ai, Xaralabos Varelas, Felicia Chen, Joseph P. Mizgerd, Alan Fine, Donal O'Carroll, Matthew R. Jones

JOURNAL OF CLINICAL INVESTIGATION ( AMER SOC CLINICAL INVESTIGATION INC )  127 ( 10 ) 3866 - 3876   2017.10 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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P-element-induced wimpy testes (Piwi) proteins are known for suppressing retrotransposon activation in the mammalian germline. However, whether Piwi protein or Piwi-dependent functions occur in the mammalian soma is unclear. Contrary to germline-restricted expression, we observed that Piwi-like Miwi2 mRNA is indeed expressed in epithelial cells of the lung in adult mice and that it is induced during pneumonia. Further investigation revealed that MIWI2 protein localized to the cytoplasm of a discrete population of multiciliated airway epithelial cells. Isolation and next-generation sequencing of MIWI2-positive multiciliated cells revealed that they are phenotypically distinct from neighboring MIWI2-negative multiciliated cells. Mice lacking MIWI2 exhibited an altered balance of airway epithelial cells, demonstrating fewer multiciliated cells and an increase in club cells. During pneumococcal pneumonia, Miwi2-deficient mice exhibited increased expression of inflammatory mediators and increased immune cell recruitment, leading to enhanced bacterial clearance. Taken together, our data delineate MIWI2-dependent functions outside of the germline and demonstrate the presence of distinct subsets of airway multiciliated cells that can be discriminated by MIWI2 expression. By demonstrating roles for MIWI2 in airway cell identity and pulmonary innate immunity, these studies elucidate unanticipated physiological functions for Piwi proteins in somatic tissues.

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Capacity of Pneumococci to Activate Macrophage Nuclear Factor κB: Influence on Necroptosis and Pneumonia Severity.

Coleman FT, Blahna MT, Kamata H, Yamamoto K, Zabinski MC, Kramnik I, Wilson AA, Kotton DN, Quinton LJ, Jones MR, Pelton SI, Mizgerd JP

The Journal of infectious diseases ( OXFORD UNIV PRESS INC )  216 ( 4 ) 425 - 435   2017.08 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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3 During pneumococcal pneumonia, antibacterial defense requires the orchestrated expression of innate immunity mediators, initiated by alveolar macrophages and dependent on transcription driven by nuclear factor kappa B (NF-kappa B). Such immune pressure may select for pneumococci, which avoid or subvert macrophage NF-kappa B activation. Analyzing pneumococci collected from children in Massachusetts, we found that the activation of macrophage NF-kappa B by Streptococcus pneumoniae is highly diverse, with a preponderance of low NF-kappa B activators that associate particularly with complicated pneumonia. Low NF-kappa B activators cause more severe lung infections in mice, and they drive macrophages toward an alternate and detrimental cell fate of necroptosis. Both outcomes can be reversed by activation of macrophages with pneumococci that are high NF-kappa B activators. These results suggest that low NF-kappa B activation is a virulence property of pneumococci and that the appropriate activation of macrophages, including NF-kappa B, may hold promise as an adjunct therapeutic avenue for pneumococcal pneumonia.

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In vitro and in vivo antifungal activities of T-2307, a novel arylamidine, against Cryptococcus gattii: an emerging fungal pathogen

Hiroshi Nishikawa, Yoshiko Fukuda, Junichi Mitsuyama, Masato Tashiro, Akitaka Tanaka, Takahiro Takazono, Tomomi Saijo, Kazuko Yamamoto, Shigeki Nakamura, Yoshifumi Imamura, Taiga Miyazaki, Hiroshi Kakeya, Yoshihiro Yamamoto, Katsunori Yanagihara, Hiroshi Mukae, Shigeru Kohno, Koichi Izumikawa

JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY ( OXFORD UNIV PRESS )  72 ( 6 ) 1709 - 1713   2017.06 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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Objectives: T-2307, a novel arylamidine, exhibits potent broad-spectrum activities against the majority of fungal pathogens. In this study, the antifungal activity of T-2307 against Cryptococcus gattii was evaluated in comparison with those of amphotericin B, fluconazole and voriconazole in vitro and in vivo. Methods: The MICs for 15 clinical isolates were determined according to CLSI guidelines and time-kill studies were performed using C. gattii YF2784. In a murine model for intranasal pulmonary infection caused by C. gattii YF2784, the test compounds were administered once daily for 7 days from 2 h or 14 days post-infection. The viable counts in the lungs and brain were determined at 21 days post-infection. Results: The MIC range, MIC50, MIC90 and geometric mean MIC of T-2307 were 0.0078-0.0625, 0.0313, 0.0625 and 0.0394 mg/L, respectively. The MIC of T-2307 was significantly lower than those of fluconazole, voriconazole and amphotericin B. T-2307 showed concentration-dependent fungicidal activity at 4 times the MIC or higher. Administration of T-2307 at 2 mg/kg/day, amphotericin B at 1 mg/kg/day and fluconazole at 160 mg/kg/day from 2 h post-infection significantly reduced viable counts in the lungs and brain. However, when the administration was started 14 days post-infection, only T-2307 significantly reduced the viable counts in both the lungs and the brain at 1 mg/kg/day. Conclusions: T-2307 shows excellent in vitro and in vivo antifungal activities against C. gattii and would be a promising new candidate for the treatment of cryptococcosis.

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A multicenter randomized controlled study on the efficacy of moxifloxacin and garenoxacin for the treatment of adult community-acquired pneumonia

Yoshifumi Imamura, Akitaka Tanaka, Masato Tashiro, Tomomi Saijo, Kazuko Yamamoto, Taiga Miyazaki, Misuzu Tsukamoto, Koichi Izumikawa, Katsunori Yanagihara, Hiroshi Mukae, Shigeru Kohno

Japanese Journal of Chemotherapy   65   168 - 174   2017.03 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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The clinical efficacy and safety of moxifloxacin (MFLX) and garenoxacin (GRNX), two respiratory qui-nolones used as key outpatient treatments for community-acquired pneumonia, were compared in a prospective multicenter randomized controlled study. The study involved 120 adults with mild or moderate community-acquired pneumonia who had visited the Second Department of Internal Medicine of Nagasaki University Hospital or any of 12 associated hospitals between May 2011 and April 2013. The subjects were randomly assigned to receive either MFLX (400 mg/day) or GRNX (400 mg/day); after up to 10 days of oral administration, the efficacy and safety results were compared between the two groups. The numbers of subjects in each analysis set were as follows: efficacy analysis, 111 (MFLX, 54; GRNX, 57); clinical efficacy at the end of treatment, 111 (MFLX, 54; GRNX, 57); bacteriological efficacy analysis, 52 (MFLX, 23; GRNX, 29); and safety analysis, 120 (MFLX, 59; GRNX, 61). The efficacy rate on the 5th to 10th day of post-treatment, defined as the primary endpoint, was 88.9% for the MFLX group and 89.5% for the GRNX group, with no statistically significant difference between the groups. Secondary endpoints, consisting of the efficacy rate on the 3rd day after the initiation of treatment (77.8% for MFLX vs. 73.7% for GRNX), the efficacy rate at the end of treatment (96.3% for MFLX vs. 93.0% for GRNX), and the bacteriological eradication rate (82.6% for MFLX vs. 96.6% for GRNX) were also comparable for both groups, with no statistically significant difference. The incidences of adverse events in the MFLX and GRNX groups were 27.1% and 31.1%, respectively, and no serious adverse events were observed. These results indicate that for the outpatient treatment of adults with mild or moderate community-acquired pneumonia, MFLX and GRNX are comparable with regard to their clinical efficacy and safety.

Epithelial Cell-Derived Secreted and Transmembrane 1a Signals to Activated Neutrophils during Pneumococcal Pneumonia

Hirofumi Kamata, Kazuko Yamamoto, Gregory A. Wasserman, Mary C. Zabinski, Constance K. Yuen, Wing Yi Lung, Adam C. Gower, Anna C. Belkina, Maria I. Ramirez, Jane C. Deng, Lee J. Quinton, Matthew R. Jones, Joseph P. Mizgerd

AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY ( AMER THORACIC SOC )  55 ( 3 ) 407 - 418   2016.09 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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Airway epithelial cell responses are critical to the outcome of lung infection. In this study, we aimed to identify unique contributions of epithelial cells during lung infection. To differentiate genes induced selectively in epithelial cells during pneumonia, we compared genome-wide expression profiles from three sorted cell populations: epithelial cells from uninfected mouse lungs, epithelial cells from mouse lungs with pneumococcal pneumonia, and nonepithelial cells from those same infected lungs. Of 1,166 transcripts that were more abundant in epithelial cells from infected lungs compared with nonepithelial cells from the same lungs or from epithelial cells of uninfected lungs, 32 genes were identified as highly expressed secreted products. Especially strong signals included two related secreted and transmembrane (Sectm) 1 genes, Sectm1a and Sectm1b. Refinement of sorting strategies suggested that both Sectm1 products were induced predominantly in conducting airway epithelial cells. Sectm1 was induced during the early stages of pneumococcal pneumonia, and mutation of NF-kappa B RelA in epithelial cells did not diminish its expression. Instead, type I IFN signaling was necessary and sufficient for Sectm1 induction in lung epithelial cells, mediated by signal transducer and activator of transcription 1. For target cells, Sectm1a bound to myeloid cells preferentially, in particular Ly6G(bright)CD11b(bright) neutrophils in the infected lung. In contrast, Sectm1a did not bind to neutrophils from uninfected lungs. Sectm1a increased expression of the neutrophil-attracting chemokine CXCL2 by neutrophils from the infected lung. We propose that Sectm1a is an epithelial product that sustains a positive feedback loop amplifying neutrophilic inflammation during pneumococcal pneumonia.

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An Autopsy Case of Lepidic Pulmonary Metastasis from Cholangiocarcinoma

Yohsuke Nagayoshi, Kazuko Yamamoto, Satoru Hashimoto, Keiko Hisatomi, Seiji Doi, Seiji Nagashima, Hirokazu Kurohama, Masahiro Ito, Takahiro Takazono, Shigeki Nakamura, Taiga Miyazaki, Shigeru Kohno

INTERNAL MEDICINE ( JAPAN SOC INTERNAL MEDICINE )  55 ( 19 ) 2849 - 2853   2016 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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We herein report the first case of pulmonary metastasis with lepidic growth that originated from cholangiocarcinoma. A 77-year-old man was admitted to our hospital due to exertional dyspnea and liver dysfunction. Computed tomography showed widespread infiltration and a ground-glass opacity in the lung and dilation of the intrahepatic bile duct. The pulmonary lesion progressed rapidly, and the patient died of respiratory failure. Cholangiocarcinoma and lepidic pulmonary metastasis were pathologically diagnosed by an autopsy. Lepidic pulmonary growth is an atypical pattern of metastasis, and immunopathological staining is useful to distinguish pulmonary metastasis from extrapulmonary cancer and primary pulmonary adenocarcinoma.

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Recurrent Streptococcus agalactiae Toxic Shock Syndrome Triggered by a Tumor Necrosis Factor-α Inhibitor.

Yoshida M, Takazono T, Tashiro M, Saijo T, Morinaga Y, Yamamoto K, Nakamura S, Imamura Y, Miyazaki T, Sawai T, Nishino T, Izumikawa K, Yanagihara K, Mukae H, Kohno S

Internal medicine (Tokyo, Japan) ( JAPAN SOC INTERNAL MEDICINE )  55 ( 21 ) 3211 - 3214   2016 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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Streptococcal toxic shock syndrome caused by group B streptococcus (GBS) is a rare, but lethal disease. We experienced a 45-year-old woman with pustular psoriasis who developed toxic shock-like syndrome during infliximab treatment. Surprisingly, similar episodes recurred three times in one year with restarting of infliximab treatments. In the third episode, GBS were detected in blood, urine, and vaginal secretion cultures. These episodes of shock syndrome were possibly due to GBS. To the best of our knowledge, this is the first case report of recurrent streptococcal toxic shock syndrome possibly caused by GBS which was induced by anti-TNF-alpha inhibitor therapy. The restarting of biological agents in patients with a history of toxic shock syndrome should therefore be avoided as much as possible.

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Relapsed Pulmonary Cryptococcosis during Tumor Necrosis Factor α Inhibitor Treatment.

Takazono T, Sawai T, Tashiro M, Saijo T, Yamamoto K, Imamura Y, Miyazaki T, Suyama N, Izumikawa K, Kakeya H, Yanagihara K, Mukae H, Kohno S

Internal medicine (Tokyo, Japan) ( JAPAN SOC INTERNAL MEDICINE )  55 ( 19 ) 2877 - 2880   2016 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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A 35-year-old non-HIV patient developed pulmonary cryptococcosis after the initiation of infliximab. He recovered by fluconazole treatment and completed the therapy for a total of 6 months. However, he experienced a relapse 16 months later during retreatment with infliximab, revealing an interesting clinical course contradicting retreatment. This case also represents the first case of relapsed pulmonary cryptococcosis suspected during treatment with a biologic agent. Both of these aspects generated important clinical questions about the length of pulmonary cryptococcosis treatment and the necessity of introducing a second prophylaxis for such patients.

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