Faculty Profiles - SHIBAYAMA Keigo

Papers - SHIBAYAMA Keigo

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A nationwide population-based surveillance of invasive Haemophilus influenzae diseases in children after the introduction of the Haemophilus influenzae type b vaccine in Japan. Reviewed International journal

Shigeru Suga, Naruhiko Ishiwada, Yuko Sasaki, Hideki Akeda, Junichiro Nishi, Kenji Okada, Mikiya Fujieda, Megumi Oda, Kazutoyo Asada, Takashi Nakano, Akihiko Saitoh, Mitsuaki Hosoya, Takehiro Togashi, Mayumi Matsuoka, Kouji Kimura, Keigo Shibayama

Vaccine Vol. 36 ( 38 ) page： 5678 - 5684 2018.9

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Haemophilus influenzae type b (Hib) vaccine was introduced as a voluntary vaccine in December 2008 and was included in the national routine immunization program in April 2013 in Japan. Currently, no nationwide data are available to evaluate the effectiveness of Hib vaccine in Japan. METHODS: To evaluate the effectiveness of Hib vaccine in Japan, nationwide active population-based surveillance of culture-proven invasive infections caused by H. influenzae in children was performed in 2008-2017 in 10 prefectures in Japan (covering approximately 23% of the total Japanese population). Clinical data were recorded on a standardized case report form. Capsular type and antimicrobial susceptibility of the H. influenzae isolates were examined. The incidence rate ratio (IRR) and its confidence interval (CI) were calculated to compare data from 5 years before and that from after the introduction of the national routine Hib vaccine immunization program. RESULTS: During the 10-year study period, 566 invasive H. influenzae disease cases including 336 meningitis cases were identified. The average number of invasive H. influenzae disease cases among children <5 years of age during 2013-2017 decreased by 93% (IRR: 0.07, 95%CI 0.05-0.10, p < 0.001) compared with those occurring during 2008-2012. Hib strains have not been isolated from invasive H. influenzae disease cases since 2014; however, non-typeable H. influenzae and H. influenzae type f isolates have been noted as causes of invasive H. influenzae diseases among children <5 years in the post-Hib vaccine era. CONCLUSIONS: After the governmental subsidization of the Hib vaccine, invasive Hib disease cases decreased dramatically in the study population, as per our surveillance. Continuous surveillance is necessary to monitor the effectiveness of Hib vaccine and for detecting any emerging invasive capsular types.

DOI： 10.1016/j.vaccine.2018.08.029

Clinical and Bacteriologic Analysis of Nontypeable Haemophilus influenzae Strains Isolated from Children with Invasive Diseases in Japan from 2008 to 2015. Reviewed International journal

Sachiko Naito, Noriko Takeuchi, Misako Ohkusu, Azusa Takahashi-Nakaguchi, Hiroki Takahashi, Naoko Imuta, Junichiro Nishi, Keigo Shibayama, Mayumi Matsuoka, Yuko Sasaki, Naruhiko Ishiwada

Journal of clinical microbiology Vol. 56 ( 7 ) page： e00141 2018.7

Language：English Publishing type：Research paper (scientific journal)

Haemophilus influenzae type b (Hib) conjugate vaccines have led to dramatic reductions in Hib disease among young children worldwide. Nontypeable H. influenzae (NTHi) is now the major cause of invasive H. influenzae infections. We investigated the clinical characteristics of invasive NTHi diseases among children in Japan, to clarify the pathogenicity of isolated NTHi strains. The mortality rate was 10.7%, with deaths occurring mainly among children with underlying comorbidities. Biotypes II and III were the most common, and most strains (64.3%) had multiple amino acid substitutions at the Asp-350, Ser-357, Ser-385, and/or Met-377 sites of penicillin-binding protein 3. Two strains were β-lactamase positive and ampicillin-clavulanate resistant. Biofilm indices varied widely, and IS1016 was detected in 10.7% of the strains tested. Moreover, there was wide variation in the characteristics of invasive NTHi strains. NTHi strains, showing great genetic diversity, are responsible for most invasive H. influenzae infections in children in the postvaccine era. Continuous monitoring of NTHi strains responsible for invasive diseases in children is important to detect changes in the epidemiology of invasive H. influenzae infections in the postvaccine era.

DOI： 10.1128/JCM.00141-18

Trends and patterns of national antimicrobial consumption in Japan from 2004 to 2016 Reviewed

Atsuko Tsutsui, Koji Yahara, Keigo Shibayama

Journal of Infection and Chemotherapy Vol. 24 ( 6 ) page： 414 - 421 2018.6

Language：English Publishing type：Research paper (scientific journal) Publisher：Elsevier B.V.

Frequent use of broad-spectrum antimicrobial classes has been reported in Japan
however, little is known about the long-term trend of national antimicrobial consumption, and that of individual agents. This study analyzed the national sales data of systemic antimicrobials from 2004 to 2016, derived from the IMS Japan Pharmaceutical Market database, to assess the consumption patterns of antimicrobial classes and agents in Japan. The number of defined daily doses per 1000 inhabitants per day (DID) was calculated for each antimicrobial agent. During the last 13 years, total antimicrobial consumption fluctuated by only 5% around the average of 14.41 DID. In 2016, the most used class was macrolides (32%), followed by cephalosporins (28%) and fluoroquinolones (19%). Oral agents comprised a large proportion (93%) of antimicrobial consumption. The most used agent, clarithromycin, accounted for 25% of all oral compounds used in 2016. The consumption of oral agents with high bioavailability, such as fluoroquinolones, amoxicillin, and sulfamethoxazole/trimethoprim increased, whereas that of cephalosporins decreased. In 2016, ceftriaxone was the most consumed parenteral agent, followed by cefazolin. The consumption of parenteral agents increased after 2009 when high-dose regimens of piperacillin/tazobactam, meropenem, and ampicillin/sulbactam were approved by the health insurance system. National antimicrobial consumption has been stable over the last 13 years. Moreover, shifts in the use of agents with high bioavailability and those approved for high-dose regimens were observed. However, the increased use of broad-spectrum agents is worrisome. A multifaceted approach is required to reduce overall antimicrobial consumption.

DOI： 10.1016/j.jiac.2018.01.003

Complete Genome Sequence of Mycobacterium marinum ATCC 927T, Obtained Using Nanopore and Illumina Sequencing Technologies. Reviewed International journal

Mitsunori Yoshida, Hanako Fukano, Yuji Miyamoto, Keigo Shibayama, Masato Suzuki, Yoshihiko Hoshino

Genome announcements Vol. 6 ( 20 ) 2018.5

Language：English Publishing type：Research paper (scientific journal)

Mycobacterium marinum is a slowly growing, broad-host-range mycobacterial species. Here, we report the complete genome sequence of a Mycobacterium marinum type strain that was isolated from tubercles of diseased fish. This sequence will provide essential information for future taxonomic and comparative genome studies of its relatives.

DOI： 10.1128/genomeA.00397-18

Genetic shifts in methicillin-resistant Staphylococcus aureus epidemic clones and toxin gene profiles in Japan: Comparative analysis among pre-epidemic, epidemic and post-epidemic phases Reviewed

Shunsuke Osaka, Katsuko Okuzumi, Shota Koide, Kiyoko Tamai, Tomoaki Sato, Koichi Tanimoto, Haruyoshi Tomita, Masahiro Suzuki, Yukiko Nagano, Keigo Shibayama, Yoshichika Arakawa, Noriyuki Nagano

Journal of Medical Microbiology Vol. 67 ( 3 ) page： 392 - 399 2018.3

Language：English Publishing type：Research paper (scientific journal) Publisher：Microbiology Society

Purpose. The decline in methicillin-resistant Staphylococcus aureus (MRSA) isolation rates has become a general observation worldwide, including Japan. We hypothesized that some genetic shift in MRSA might cause this phenomenon, and therefore we investigated the genetic profiles among MRSA clinical isolates obtained from three different epidemic phases in Japan. Methodology. A total of 353 MRSA isolates were selected from 202 medical facilities in 1990 (pre-epidemic phase), 2004 (epidemic phase) and 2016 (post-epidemic phase). Molecular typing was performed by PCR detection of 22 genes using the polymerase chain reaction (PCR)-based ORF typing (POT) system, including an additional eight genes including small genomic islets and seven toxin genes. Results. Isolates with a POT1 of score 93, identified as presumed clonal complex (pCC)5-staphylococcal cassette chromosome mec (SCCmec) type II including ST5-SCCmec type II New York/Japan clone, represented the major epidemic MRSA lineage in 1990 and 2004. In 2016, however, a marked decrease in isolates with a POT1 score of 93, along with changes in the epidemiology of toxin genes carried, was noted, where the carriers of tst genes including the tst-sec combination were markedly reduced, and those possessing the seb gene alone were markedly increased. Rather, isolates with a POT1 score of 106, including pCC1 or pCC8 among the isolates with SCCmec type IV, which often links to communityassociated MRSA, were predominant. Interestingly, the pCC1 and pCC8 lineages were related to sea and tst-sec carriage, respectively. Conclusions. Over time, a transition in MRSA genetic profiles from a POT1 score of 93 in 1990 and 2004 to 106 in 2014 was found in Japan.

DOI： 10.1099/jmm.0.000687

Rapid and easy detection of low-level resistance to vancomycin in methicillin-resistant staphylococcus aureus by matrix-assisted laser desorption ionization time-of-flight mass spectrometry Reviewed

Kota Asakura, Takuya Azechi, Hiroshi Sasano, Hidehito Matsui, Hideaki Hanaki, Motoyasu Miyazaki, Tohru Takata, Miwa Sekine, Tomoiku Takaku, Tomonori Ochiai, Norio Komatsu, Keigo Shibayama, Yuki Katayama, Koji Yahara

PLoS ONE Vol. 13 ( 3 ) page： e0194212 2018.3

Language：English Publishing type：Research paper (scientific journal) Publisher：Public Library of Science

Vancomycin-intermediately resistant Staphylococcus aureus (VISA) and heterogeneous VISA (hVISA) are associated with treatment failure. hVISA contains only a subpopulation of cells with increased minimal inhibitory concentrations, and its detection is problematic because it is classified as vancomycin-susceptible by standard susceptibility testing and the gold-standard method for its detection is impractical in clinical microbiology laboratories. Recently, a research group developed a machine-learning classifier to distinguish VISA and hVISA from vancomycin-susceptible S. aureus (VSSA) according to matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS) data. Nonetheless, the sensitivity of hVISA classification was found to be 76%, and the program was not completely automated with a graphical user interface. Here, we developed a more accurate machine-learning classifier for discrimination of hVISA from VSSA and VISA among MRSA isolates in Japanese hospitals by means of MALDI-TOF MS data. The classifier showed 99% sensitivity of hVISA classification. Furthermore, we clarified the procedures for preparing samples and obtaining MALDI-TOF MS data and developed all-in-one software, hVISA Classifier, with a graphical user interface that automates the classification and is easy for medical workers to use
it is publicly available at https://github.com/bioprojects/hVISAclassifier. This system is useful and practical for screening MRSA isolates for the hVISA phenotype in clinical microbiology laboratories and thus should improve treatment of MRSA infections.

DOI： 10.1371/journal.pone.0194212

Complete Genome Sequence of a Type Strain of Mycobacterium abscessus subsp. bolletii, a Member of the Mycobacterium abscessus Complex. Reviewed International journal

Mitsunori Yoshida, Hanako Fukano, Yuji Miyamoto, Keigo Shibayama, Masato Suzuki, Yoshihiko Hoshino

Genome announcements Vol. 6 ( 5 ) 2018.2

Language：English Publishing type：Research paper (scientific journal)

Mycobacterium abscessus subsp. bolletii is a rapidly growing mycobacterial organism for which the taxonomy is unclear. Here, we report the complete genome sequence of a Mycobacterium abscessus subsp. bolletii type strain. This sequence will provide essential information for future taxonomic and comparative genome studies of these mycobacteria.

DOI： 10.1128/genomeA.01530-17

Distribution and Molecular Characterization of Acinetobacter baumannii International Clone II Lineage in Japan. Reviewed International journal

Mari Matsui, Masato Suzuki, Masahiro Suzuki, Jun Yatsuyanagi, Masanori Watahiki, Yoichi Hiraki, Fumio Kawano, Atsuko Tsutsui, Keigo Shibayama, Satowa Suzuki

Antimicrobial agents and chemotherapy Vol. 62 ( 2 ) 2018.2

Language：English Publishing type：Research paper (scientific journal)

Multidrug-resistant (MDR) Acinetobacter spp. have been globally disseminated in association with the successful clonal lineage Acinetobacter baumannii international clone II (IC II). Because the prevalence of MDR Acinetobacter spp. in Japan remains very low, we characterized all Acinetobacter spp. (n = 866) from 76 hospitals between October 2012 and March 2013 to describe the entire molecular epidemiology of Acinetobacter spp. The most prevalent species was A. baumannii (n = 645; 74.5%), with A. baumannii IC II (n = 245) accounting for 28.3% of the total. Meropenem-resistant isolates accounted for 2.0% (n = 17) and carried ISAba1-blaOXA-23-like (n = 10), blaIMP (n = 4), or ISAba1-blaOXA-51-like (n = 3). Multilocus sequence typing of 110 representative A. baumannii isolates revealed the considerable prevalence of domestic sequence types (STs). A. baumannii IC II isolates were divided into the domestic sequence type 469 (ST469) (n = 18) and the globally disseminated STs ST208 (n = 14) and ST219 (n = 4). ST469 isolates were susceptible to more antimicrobial agents, while ST208 and ST219 overproduced the intrinsic AmpC β-lactamase. A. baumannii IC II and some A. baumannii non-IC II STs (e.g., ST149 and ST246) were associated with fluoroquinolone resistance. This study revealed that carbapenem-susceptible A. baumannii IC II was moderately disseminated in Japan. The low prevalence of acquired carbapenemase genes and presence of domestic STs could contribute to the low prevalence of MDR A. baumannii A similar epidemiology might have appeared before the global dissemination of MDR epidemic lineages. In addition, fluoroquinolone resistance associated with A. baumannii IC II may provide insight into the significance of A. baumannii epidemic clones.

DOI： 10.1128/AAC.02190-17

Mutations in Genes Encoding Penicillin-Binding Proteins and Efflux Pumps Play a Role in β-Lactam Resistance in Helicobacter cinaedi. Reviewed International journal

Emiko Rimbara, Shigetarou Mori, Hyun Kim, Masato Suzuki, Keigo Shibayama

Antimicrobial agents and chemotherapy Vol. 62 ( 2 ) 2018.2

Language：English Publishing type：Research paper (scientific journal)

β-Lactams are often used to treat Helicobacter cinaedi infections; however, the mechanism underlying β-lactam resistance is unknown. In this study, we investigated β-lactam resistance in an H. cinaedi strain, MRY12-0051 (MICs of amoxicillin [AMX] and ceftriaxone [CRO], 32 and 128 μg/ml; obtained from human feces). Based on a comparative whole-genome analysis of MRY12-0051 and the CRO-susceptible H. cinaedi strain MRY08-1234 (MICs of AMX and CRO, 1 and 4 μg/ml; obtained from human blood), we identified five mutations in genes encoding penicillin-binding proteins (PBPs), including two in pbpA, one in pbp2, and two in ftsI Transformation and penicillin binding assays indicated that CRO resistance was mainly associated with mutations in pbpA; mutations in ftsI also led to increased resistance to AMX. Knocking out cmeB and cmeD, which encode resistance-nodulation-division-type efflux pump components, in H. cinaedi type strain CCUG18818 (AMX MIC, 4 to 8 μg/ml) resulted in 8- and 64-fold decreases, respectively, in the AMX MIC. Hence, MICs of AMX in H. cinaedi become similar to those of Helicobacter pylori isolates in the absence of cmeD In conclusion, the difference in susceptibility to β-lactams between H. pylori and H. cinaedi is explained by differences in efflux pump components. Mutations in pbpA are the primary determinant of high resistance to β-lactams in H. cinaedi.

DOI： 10.1128/AAC.02036-17

The plasmid-encoded transcription factor ArdK contributes to the repression of the IMP-6 metallo-β-lactamase gene blaIMP-6, leading to a carbapenem-susceptible phenotype in the blaIMP-6-positive Escherichia coli strain A56-1S. Reviewed International journal

Takaya Segawa, Tsuyoshi Sekizuka, Satowa Suzuki, Keigo Shibayama, Mari Matsui, Makoto Kuroda

PloS one Vol. 13 ( 12 ) page： e0208976 2018

Language：English Publishing type：Research paper (scientific journal)

Carbapenemase-producing Enterobacteriaceae (CPE) are a global concern because these bacteria are resistant to almost all β-lactams. Horizontal interspecies gene transfer via plasmid conjugation has increased the global dissemination of CPE. Recently, an Enterobacteriaceae strain positive for carbapenemase gene but showing a carbapenem-susceptible phenotype was identified, suggesting that these susceptible strains may be challenging to detect solely via antimicrobial susceptibility tests without molecular analysis. Here, we isolated a blaIMP-6 carbapenemase-gene positive but imipenem- and meropenem-susceptible Escherichia coli (ISMS-E) strain A56-1S (imipenem and meropenem minimum inhibitory concentration, ≤ 0.125 mg/L), from a human urine specimen in Japan. A56-1S was carbapenemase negative by the Carba NP test, suggesting that IMP-6 production was low or undetectable. Thus, to characterize the mechanism of this phenotype, a meropenem-resistant E. coli A56-1R strain was obtained using meropenem-selection. A56-1R was positive for carbapenemase production by the Carba NP test, and blaIMP-6 transcription in A56-1R was 53-fold higher than in A56-1S, indicating that blaIMP-6 in A56-1S is negatively regulated at the transcriptional level. Comparative genomic analysis between the two strains revealed that the alleviation of restriction of DNA (ardK) gene encoding a putative transcription factor is disrupted by the IS26 insertion in A56-1R. A cotransformation assay of ardK and the regulatory element upstream of blaIMP-6 showed repression of blaIMP-6 transcription, indicating that ArdK negatively modulates blaIMP-6 transcription. ArdK binding and affinity assays demonstrated that ArdK directly binds to the regulatory element upstream of blaIMP-6 with dissociation constant values comparable to those of general transcription factors. The IMP-6 carbapenemase showed low hydrolytic activity against imipenem, resulting in an imipenem-susceptible and meropenem-resistant (ISMR) phenotype (previously reported as a stealth phenotype). However, the low expression of IMP-6 in the A56-1S strain could be a typical characteristic of ISMS-E due to gene repression, indicating that conventional antimicrobial susceptibility tests might be unable to detect such strains even when using both imipenem and meropenem. Bacteria that exhibit the ISMS phenotype could play a potential role as undetectable reservoirs and might facilitate gene transfer to other organisms while avoiding detection.

DOI： 10.1371/journal.pone.0208976

Draft genome sequence of Mycobacterium sp. strain shizuoka-1, a novel mycobacterium isolated from groundwater of a bathing facility in Shizuoka, Japan Reviewed

Mitsunori Yoshida, Shinji Izumiyama, Hanako Fukano, Kanji Sugiyama, Masato Suzuki, Keigo Shibayama, Yoshihiko Hoshino

Genome Announcements Vol. 5 ( 47 ) 2017.11

Language：English Publishing type：Research paper (scientific journal) Publisher：American Society for Microbiology

Mycobacterium sp. strain shizuoka-1 is a rapidly growing scotochromogenic mycobacterium and was isolated from well water for a bathing facility in Shizuoka Prefecture in Japan. Here, we report the draft sequence of its genome, comprising a 6.5-Mb chromosome. This mycobacterium has 83.1% identity with Mycobacterium rhodesiae, a human pathogen.

DOI： 10.1128/genomeA.01309-17

Venom and Antivenom of the Redback Spider (Latrodectus hasseltii) in Japan. Part II. Experimental Production of Equine Antivenom against the Redback Spider Reviewed

Shigemi Mori, Akira Horita, Akihiro Ginnaga, Yoshinobu Miyatsu, Kyoko Sawabe, Takayuki Matsumura, Manabu Ato, Akihiko Yamamoto, Keigo Shibayama, Satoru Arai, Takuya Yamagishi, Motohide Takahashi, Hisashi Taki, Toru Hifumi

JAPANESE JOURNAL OF INFECTIOUS DISEASES Vol. 70 ( 6 ) page： 635 - 641 2017.11

Language：English Publishing type：Research paper (scientific journal) Publisher：NATL INST INFECTIOUS DISEASES

This is the first report on large-scale experimental production of an equine antivenom against the redback spider (Latrodectus hasseltii) lived in Japan. We captured 10,000 redback spiders in Japan and prepared the toxoids of crude venom extract, mixed the toxoids with a mineral oil adjuvant, and immunized healthy horses repeatedly over a period of several weeks. Thereafter, we separated the horse plasma, purified the gamma-globulin fraction, and stocked it as a purified antivenom concentrate. Consequently, we manufactured approximately 6,500 vials of a single-dose freeze-dried test lot from a portion of the purified gamma-globulin fraction, equivalent to the extract derived from 520 spiders. This test lot had an antitoxin titer comparable to that of a similar drug commercially available overseas (a liquid preparation), and the other quality met all quality reference specifications based on the Minimum Requirements for Biological Products and other guidelines relevant to existing antivenom drug products in Japan.

DOI： 10.7883/yoken.JJID.2017.125

Diversity and microevolution of CRISPR loci in Helicobacter cinaedi Reviewed

Junko Tomida, Yuji Morita, Keigo Shibayama, Ken Kikuchi, Tomohiro Sawa, Takaaki Akaike, Yoshiaki Kawamura

PLOS ONE Vol. 12 ( 10 ) page： e0186241 2017.10

Language：English Publishing type：Research paper (scientific journal) Publisher：PUBLIC LIBRARY SCIENCE

Helicobacter cinaedi is associated with nosocomial infections. The CRISPR-Cas system provides adaptive immunity against foreign genetic elements. We investigated the CRISPR-Cas system in H. cinaedi to assess the potential of the CRISPR-based microevolution of H. cinaedi strains. A genotyping method based on CRISPR spacer organization was carried out using 42 H. cinaedi strains. The results of sequence analysis showed that the H. cinaedi strains used in this study had two CRISPR loci (CRISPR1 and CRISPR2). The lengths of the consensus direct repeat sequences in CRISPR1 and CRISPR2 were both 36 bp-long, and 224 spacers were found in the 42 H. cinaedi strains. Analysis of the organization and sequence similarity of the spacers of the H. cinaedi strains showed that CRISPR arrays could be divided into 7 different genotypes. Each genotype had a different ancestral spacer, and spacer acquisition/deletion events occurred while isolates were spreading. Spacer polymorphisms of conserved arrays across the strains were instrumental for differentiating closely-related strains collected from the same hospital. MLST had little variability, while the CRISPR sequences showed remarkable diversity. Our data revealed the structural features of H. cinaedi CRISPR loci for the first time. CRISPR sequences constitute a valuable basis for genotyping, provide insights into the divergence and relatedness between closelyrelated strains, and reflect the microevolutionary process of H. cinaedi.

DOI： 10.1371/journal.pone.0186241

Integration of DPC and clinical microbiological data in Japan reveals importance of confirming a negative follow-up blood culture in patients with MRSA bacteremia Reviewed

Naoki Miyamoto, Koji Yahara, Rie Horita, Tomomi Yano, Naotaka Tashiro, Daiichi Morii, Atsuko Tsutsui, Kenichiro Yaita, Keigo Shibayama, Hiroshi Watanabe

JOURNAL OF INFECTION AND CHEMOTHERAPY Vol. 23 ( 10 ) page： 687 - 691 2017.10

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER SCIENCE BV

Methicillin-resistant Staphylococcus aureus (MRSA) bacteremia is one of the commonest and most life-threatening of all infectious diseases. The morbidity and mortality rates associated with MRSA bacteremia are higher than those associated with bacteremia caused by other pathogens. A common guideline in MRSA bacteremia treatment is to confirm bacteremia clearance through additional blood cultures 2-4 days after initial positive cultures and as needed thereafter. However, no study has presented statistical evidence of how and to what extent confirming a negative follow-up blood culture impacts clinical outcome. We present this evidence for the first time, by combining clinical microbiological data of blood cultures and the DPC administrative claims database; both had been systematically accumulated through routine medical care in hospitals. We used electronic medical records to investigate the clinical background and infection source in detail. By analyzing data from a university hospital, we revealed how survival curves change when a negative follow-up blood culture is confirmed. We also demonstrated confirmation of a negative culture is significantly associated with clinical outcomes: there was a more than three-fold increase in mortality risk (after adjusting for clinical background) if a negative blood culture was not confirmed within 14 days of the initial positive blood culture. Although we used data from only one university hospital, our novel approach and results will be a basis for future studies in several hospitals in Japan to provide statistical evidence of the clinical importance of confirming a negative follow-up blood culture in bacteremia patients, including those with MRSA infections. (C) 2017 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.jiac.2017.07.009

Molecular epidemiology of Bordetella pertussis in Cambodia determined by direct genotyping of clinical specimens Reviewed

Takumi Moriuchi, Ork Vichit, Yong Vutthikol, Md. Shafiqul Hossain, Chham Samnang, Kohei Toda, Varja Grabovac, Yukihiro Hiramatsu, Nao Otsuka, Keigo Shibayama, Kazunari Kamachi

INTERNATIONAL JOURNAL OF INFECTIOUS DISEASES Vol. 62 page： 56 - 58 2017.9

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER SCI LTD

Objectives: This study sought to determine the genotypes of circulating Bordetella pertussis, the causative agent of pertussis, in Cambodia by direct molecular typing of clinical specimens.
Methods: DNA extracts from nasopharyngeal swabs obtained from 82 pertussis patients in 20082016 were analyzed by multilocus variable-number tandem repeat analysis (MLVA). B. pertussis virulence-associated allelic genes (ptxA, prn, and fim3) and the pertussis toxin promoter ptxP were also investigated by DNA sequence-based typing.
Results: Forty-four DNA extracts (54%) yielded a complete MLVA profile, and these were sorted into 8 MLVA types (MT18, MT26, MT27, MT29, MT43, MT72, MT95, and MT200). MT27 and MT29, which are common in developed countries, were the predominant strain types (total 73%). The predominant profile of virulence-associated allelic genes was the combination of ptxP3/ptxA1/prn2/fim3A (48%). MT27 strains were detected during the entire study period, whereas MT29 strains were only found in 2014-2016.
Conclusions: The B. pertussis population in Cambodia, where a whole-cell pertussis vaccine (WCV) has been continuously used, resembled those observed previously in developed countries where acellular pertussis vaccines are used. Circulating B. pertussis strains in Cambodia were distinct from those in other countries using WCVs. (C) 2017 The Author(s). Published by Elsevier Ltd on behalf of International Society for Infectious Diseases.

DOI： 10.1016/j.ijid.2017.07.015

Analysis of multidrug resistant group B streptococci with reduced penicillin susceptibility forming small, less hemolytic colonies Reviewed

Hirotsugu Banno, Kouji Kimura, Yosuke Tanaka, Tsuyoshi Sekizuka, Makoto Kuroda, Wanchun Jin, Jun-ichi Wachino, Keiko Yamada, Keigo Shibayama, Yoshichika Arakawa

PLOS ONE Vol. 12 ( 8 ) page： e0183453 2017.8

Language：English Publishing type：Research paper (scientific journal) Publisher：PUBLIC LIBRARY SCIENCE

Group B streptococci (GBS; Streptococcus agalactiae) are the leading cause of neonatal invasive diseases and are also important pathogens for elderly adults. Until now, nearly all GBS with reduced penicillin susceptibility (PRGBS) have shown beta-hemolytic activity and grow on sheep blood agar. However, we have previously reported three PRGBS clinical isolates harboring a CylK deletion that form small less hemolytic colonies. In this study, we examined the causes of small, less hemolytic colony formation in these clinical isolates. Isogenic strains were sequenced to identify the mutation related to a small colony size. We identified a 276_277insG nucleic acid insertion in the thiamin pyrophosphokinase (tpk) gene, resulting in premature termination at amino acid 103 in TPK, as a candidate mutation responsible for small colony formation. The recombinant strain Delta tpk, which harbored the 276_277insG insertion in the tpk gene, showed small colony formation. The recombinant strain.cylK, which harbored the G379T substitution in cylK, showed a reduction in hemolytic activity. The phenotypes of both recombinant strains were complemented by the expression of intact TPK or CylK, respectively. Moreover, the use of Rapid ID 32 API and VITEK MS to identify strains as GBS was evaluated clinical isolates and recombinant strains. VITEK MS, but not Rapid ID 32 API, was able to accurately identify the strains as GBS. In conclusion, we determined that mutations in tpk and cylK caused small colonies and reduced hemolytic activity, respectively, and characterized the clinical isolates in detail.

DOI： 10.1371/journal.pone.0183453

A high seroprevalence of antibodies to pertussis toxin among Japanese adults: Qualitative and quantitative analyses Reviewed

Takumi Moriuchi, Nao Otsuka, Yukihiro Hiramatsu, Keigo Shibayama, Kazunari Kamachi

PLOS ONE Vol. 12 ( 7 ) page： e0181181 2017.7

Language：English Publishing type：Research paper (scientific journal) Publisher：PUBLIC LIBRARY SCIENCE

In 2013, national serosurveillance detected a high seroprevalence of antibodies to pertussis toxin ( PT) from Bordetella pertussis among Japanese adults. Thus, we aimed to determine the cause(s) of this high seroprevalence, and analyzed the titers of antibodies to PT and filamentous hemagglutinin (FHA) among adults (35-44 years old), young children (4-7 years old), and older children (10-14 years old). Our quantitative analyses revealed that adults had higher seroprevalences of anti-PT IgG and PT-neutralizing antibodies, and similar titers of anti-FHA IgG, compared to the young and older children. Positive correlations were observed between the titers of PT-neutralizing antibodies and anti-PT IgG in all age groups (rs values of 0.326-0.522), although the correlation tended to decrease with age. The ratio of PT-neutralizing antibodies to anti-PT IgG was significantly different when we compared the serum and purified IgG fractions among adults (p = 0.016), although this result was not observed among young and older children. Thus, it appears that some adults had non-IgG immunoglobulins to PT. Our analyses also revealed that adults had high-avidity anti-PT IgG ( avidity index: 63.5%, similar results were observed among the children); however, the adults had lower-avidity anti-FHA IgG (37.9%, p < 0.05). It is possible that low-avidity antiFHA IgG is related to infection with other respiratory pathogens (e.g., Bordetella parapertussis, Haemophilus influenzae, or Mycoplasma pneumoniae), which produces antibodies to FHA-like proteins. Our observations suggest that these adults had been infected with B. pertussis and other pathogen(s) during their adulthood.

DOI： 10.1371/journal.pone.0181181

Antibiotic Susceptibilities and Genetic Characteristics of Extended-Spectrum Beta-Lactamase-Producing Escherichia coli Isolates from Stools of Pediatric Diarrhea Patients in Surabaya, Indonesia Reviewed

Eddy Bagus Wasitou, Katsumi Shigemura, Kayo Osawa, Alpha Fardah, Akiho Kanaida, Dadik Raharjo, K. Kuntaman, Usman Hadi, Sugeng Harijono, Subijanto Marto Sudarmo, Tatsuya Nakamura, Keigo Shibayama, Masato Fujisawa, Toshiro Shirakawa

JAPANESE JOURNAL OF INFECTIOUS DISEASES Vol. 70 ( 4 ) page： 378 - 382 2017.7

Language：English Publishing type：Research paper (scientific journal) Publisher：NATL INST INFECTIOUS DISEASES

The purpose of this study was to investigate extended-spectrum beta-lactamase (ES-BL)-producing Escherichia coli isolates from pediatric (aged 0 to 3 years) diarrhea patients in Surabaya, Indonesia, where this kind of survey is rare; our study included assessment of their antibiotic susceptibilides, as well as ESBL typing, multilocus sequence typing (MLST), and diarrheagenic E. coli (DEC)-typing. ESBL-producing E. coli were detected in 18.8% of all the samples. Many ESBL-producing E. coli had significantly lower susceptibility to gentamicin (p < 0.0001) and the quinolones nalidixic acid (p = 0.004) and ciprofloxacin (p < 0.0001) than non-producers. In ESBL-producing E. coli, 84.0% of strains expressed CTX-M-15 alone or in combination with other ESBL types. MLST revealed that 24.0% of ESBL-producers had sequence type 617, all of which expressed the CTX-M-15 gene; we also detected expression of 3 DEC-related genes: 2 enteroaggregative E. coli genes and 1 enteropathogenic E. coli gene. In conclusion, CTX-M-15-type ESBL-producing E. coli ST617 appear to have spread to Indonesia.

DOI： 10.7883/yoken.JJID6.234

Biochemical and structural investigations on phosphoribosylpyrophosphate synthetase from Mycobacterium smegmatis Reviewed

Stefano Donini, Silvia Garavaglia, Davide M. Ferraris, Riccardo Miggiano, Shigetarou Mori, Keigo Shibayama, Menico Rizzi

PLOS ONE Vol. 12 ( 4 ) page： e0175815 2017.4

Language：English Publishing type：Research paper (scientific journal) Publisher：PUBLIC LIBRARY SCIENCE

Mycobacterium smegmatis represents one model for studying the biology of its pathogenic relative Mycobacterium tuberculosis. The structural characterization of a M. tuberculosis ortholog protein can serve as a valid tool for the development of molecules active against the M. tuberculosis target. In this context, we report the biochemical and structural characterization of M. smegmatis phosphoribosylpyrophosphate synthetase (PrsA), the ortholog of M. tuberculosis PrsA, the unique enzyme responsible for the synthesis of phosphoribosylpyrophosphate (PRPP). PRPP is a key metabolite involved in several biosynthetic pathways including those for histidine, tryptophan, nucleotides and decaprenylphosphoryl-arabinose, an essential precursor for the mycobacterial cell wall biosynthesis. Since M. tuberculosis PrsA has been validated as a drug target for the development of antitubercular agents, the data presented here will add to the knowledge of the mycobacterial enzyme and could contribute to the development of M. tuberculosis PrsA inhibitors of potential pharmacological interest.

DOI： 10.1371/journal.pone.0175815

Significant Decrease in Pertactin-Deficient Bordetella pertussis Isolates, Japan Reviewed

Yukihiro Hiramatsu, Yusuke Miyaji, Nao Otsuka, Yoshichika Arakawa, Keigo Shibayama, Kazunari Kamachi

EMERGING INFECTIOUS DISEASES Vol. 23 ( 4 ) page： 699 - 701 2017.4

Language：English Publishing type：Research paper (scientific journal) Publisher：CENTERS DISEASE CONTROL

Prevalence of pertactin-lacking Bordetella pertussis isolates has been observed worldwide. In Japan, however, we found that the frequency of pertactin-deficient isolates in 2014-2016 (8%) was significantly lower than the frequency in 2005-2007 (41%), 2008-2010 (35%), and 2011-2013 (25%). This reduction was closely associated with changes in genotypes.

DOI： 10.3201/eid2304.161575

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