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      Multi-step genomic dissection of a suspected intra-hospital Helicobacter cinaedi outbreak

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          Helicobacter cinaedi is an emerging pathogen causing bacteraemia and cellulitis. Nosocomial transmission of this microbe has been described, but detailed molecular-epidemiological analyses have not been performed. Here, we describe the results of a multi-step genome-wide phylogenetic analysis of a suspected intra-hospital outbreak of H. cinaedi that occurred in a hospital in Japan. The outbreak was recognized by the infectious control team (ICT) of the hospital as a sudden increase in H. cinaedi bacteraemia. ICT defined this outbreak case based on 16S rRNA sequence data and epidemiological information, but were unable to determine the source and route of the infections. We therefore re-investigated this case using whole-genome sequencing (WGS). We first performed a species-wide analysis using publicly available genome sequences to understand the level of genomic diversity of this under-studied species. The clusters identified were then separately analysed using the genome sequence of a representative strain in each cluster as a reference. These analyses provided a high-level phylogenetic resolution of each cluster, identified a confident set of outbreak isolates, and discriminated them from other closely related but distinct clones, which were locally circulating and invaded the hospital during the same period. By considering the epidemiological data, possible strain transmission chains were inferred, which highlighted the role of asymptomatic carriers or environmental contamination. The emergence of a subclone with increased resistance to fluoroquinolones in the outbreak was also recognized. Our results demonstrate the impact of the use of a closely related genome as a reference to maximize the power of WGS.

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          Most cited references 43

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          Tracking a hospital outbreak of carbapenem-resistant Klebsiella pneumoniae with whole-genome sequencing.

          The Gram-negative bacteria Klebsiella pneumoniae is a major cause of nosocomial infections, primarily among immunocompromised patients. The emergence of strains resistant to carbapenems has left few treatment options, making infection containment critical. In 2011, the U.S. National Institutes of Health Clinical Center experienced an outbreak of carbapenem-resistant K. pneumoniae that affected 18 patients, 11 of whom died. Whole-genome sequencing was performed on K. pneumoniae isolates to gain insight into why the outbreak progressed despite early implementation of infection control procedures. Integrated genomic and epidemiological analysis traced the outbreak to three independent transmissions from a single patient who was discharged 3 weeks before the next case became clinically apparent. Additional genomic comparisons provided evidence for unexpected transmission routes, with subsequent mining of epidemiological data pointing to possible explanations for these transmissions. Our analysis demonstrates that integration of genomic and epidemiological data can yield actionable insights and facilitate the control of nosocomial transmission.
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            Rapid whole-genome sequencing for investigation of a neonatal MRSA outbreak.

            Isolates of methicillin-resistant Staphylococcus aureus (MRSA) belonging to a single lineage are often indistinguishable by means of current typing techniques. Whole-genome sequencing may provide improved resolution to define transmission pathways and characterize outbreaks. We investigated a putative MRSA outbreak in a neonatal intensive care unit. By using rapid high-throughput sequencing technology with a clinically relevant turnaround time, we retrospectively sequenced the DNA from seven isolates associated with the outbreak and another seven MRSA isolates associated with carriage of MRSA or bacteremia in the same hospital. We constructed a phylogenetic tree by comparing single-nucleotide polymorphisms (SNPs) in the core genome to a reference genome (an epidemic MRSA clone, EMRSA-15 [sequence type 22]). This revealed a distinct cluster of outbreak isolates and clear separation between these and the nonoutbreak isolates. A previously missed transmission event was detected between two patients with bacteremia who were not part of the outbreak. We created an artificial "resistome" of antibiotic-resistance genes and demonstrated concordance between it and the results of phenotypic susceptibility testing; we also created a "toxome" consisting of toxin genes. One outbreak isolate had a hypermutator phenotype with a higher number of SNPs than the other outbreak isolates, highlighting the difficulty of imposing a simple threshold for the number of SNPs between isolates to decide whether they are part of a recent transmission chain. Whole-genome sequencing can provide clinically relevant data within a time frame that can influence patient care. The need for automated data interpretation and the provision of clinically meaningful reports represent hurdles to clinical implementation. (Funded by the U.K. Clinical Research Collaboration Translational Infection Research Initiative and others.).
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              Mechanisms of resistance to quinolones: target alterations, decreased accumulation and DNA gyrase protection.

               Joaquim Ruiz (2003)
              Quinolones are broad-spectrum antibacterial agents, commonly used in both clinical and veterinary medicine. Their extensive use has resulted in bacteria rapidly developing resistance to these agents. Two mechanisms of quinolone resistance have been established to date: alterations in the targets of quinolones, and decreased accumulation due to impermeability of the membrane and/or an overexpression of efflux pump systems. Recently, mobile elements have also been described, carrying the qnr gene, which confers resistance to quinolones.

                Author and article information

                Microb Genom
                Microb Genom
                Microbial Genomics
                Microbiology Society
                January 2019
                17 January 2019
                17 January 2019
                : 5
                : 1
                [ 1]Department of Bacteriology, Faculty of Medical Sciences, Kyushu University , Fukuoka, Japan
                [ 2]Previous address: Division of Microbiology, Department of Infectious Diseases, Faculty of Medicine, University of Miyazaki , Miyazaki, Japan
                [ 3]Laboratory of Veterinary Public Health, Department of Veterinary Medical Science, Faculty of Agriculture, University of Miyazaki , Miyazaki, Japan
                [ 4]Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology , Tokyo, Japan
                [ 5]Frontier Science Research Center, University of Miyazaki , Miyazaki, Japan
                [ 6]Center for Infection Control, University of Miyazaki Hospital , Miyazaki, Japan
                [ 7]Department of Microbiology, School of Pharmacy, Aichi Gakuin University , Nagoya, Japan
                [ 8]Faculty of Agriculture, University of Miyazaki Center for Animal Disease Control, University of Miyazaki , Miyazaki, Japan
                [ 9]Department of Rheumatology, Infectious Diseases and Laboratory Medicine, University of Miyazaki , Miyazaki, Japan
                Author notes
                *Correspondence: Tetsuya Hayashi, thayash@
                © 2019 The Authors

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                Funded by: Integrated Research Project for Human and Veterinary Medicine of the University of Miyazaki
                Funded by: JSPS KAKENHI
                Award ID: JP25670468
                Funded by: JSPS KAKENHI
                Award ID: JP17K17933
                Research Article
                Microbial Evolution and Epidemiology: Communicable Disease Genomics
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