Publications by authors named "Glen P Carter"

55 Publications

Genomic Insights Into Last-Line Antimicrobial Resistance in Multidrug-Resistant and Vancomycin-Resistant .

Front Microbiol 2021 16;12:637656. Epub 2021 Mar 16.

Department of Microbiology and Immunology, Doherty Institute, The University of Melbourne, Melbourne, VIC, Australia.

Multidrug-resistant and vancomycin-resistant (VRE) are important human pathogens that are resistant to most clinical antibiotics. Treatment options are limited and often require the use of 'last-line' antimicrobials such as linezolid, daptomycin, and in the case of , also vancomycin. The emergence of resistance to these last-line antimicrobial agents is therefore of considerable clinical concern. This mini-review provides an overview of resistance to last-line antimicrobial agents in and VRE, with a particular focus on how genomics has provided critical insights into the emergence of resistant clones, the molecular mechanisms of resistance, and the importance of mobile genetic elements in the global spread of resistance to linezolid.
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http://dx.doi.org/10.3389/fmicb.2021.637656DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8007764PMC
March 2021

Clinical relevance of topical antibiotic use in co-selecting for multidrug-resistant : Insights from and models.

Antimicrob Agents Chemother 2021 Feb 16. Epub 2021 Feb 16.

Department of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, Australia

Topical antibiotic preparations, such as fusidic acid (FA) or mupirocin, are used in the prevention and treatment of superficial skin infections caused by staphylococci. Previous genomic epidemiology work has suggested an association between the widespread use of topical antibiotics and the emergence of methicillin resistant in some settings. In this study, we provide experimental proof of co-selection for multidrug resistance in following exposure to FA or mupirocin. Through targeted mutagenesis and phenotypic analyses, we confirmed that carriage confers resistance to FA, and carriage confers high-level resistance to mupirocin in multiple genetic backgrounds. experiments demonstrated that carriage of and confer a competitive advantage in the presence of sub-inhibitory concentrations of FA and mupirocin, respectively. Further, we used a porcine skin colonisation model to show that clinically relevant concentrations of topical antibiotics can co-select for presence of unrelated antimicrobial resistance determinants, such as , , and , in or harbouring These findings provide valuable insights on the role of acquired FA or mupirocin resistance in co-selecting for broader antibiotic resistance in , prompting greater need for judicious use of topical antibiotics.
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http://dx.doi.org/10.1128/AAC.02048-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8092865PMC
February 2021

Complete microbial genomes for public health in Australia and the Southwest Pacific.

Microb Genom 2020 12 12;6(12). Epub 2020 Nov 12.

Department of Microbiology and Immunology, The University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Parkville, Victoria 3001, Australia.

Complete genomes of microbial pathogens are essential for the phylogenomic analyses that increasingly underpin core public health laboratory activities. Here, we announce a BioProject (PRJNA556438) dedicated to sharing complete genomes chosen to represent a range of pathogenic bacteria with regional importance to Australia and the Southwest Pacific; enriching the catalogue of globally available complete genomes for public health while providing valuable strains to regional public health microbiology laboratories. In this first step, we present 26 complete high-quality bacterial genomes. Additionally, we describe here a framework for reconstructing complete microbial genomes and highlight some of the challenges and considerations for accurate and reproducible genome reconstruction.
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http://dx.doi.org/10.1099/mgen.0.000471DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8116684PMC
December 2020

Microbe-Metabolite Associations Linked to the Rebounding Murine Gut Microbiome Postcolonization with Vancomycin-Resistant Enterococcus faecium.

mSystems 2020 Aug 18;5(4). Epub 2020 Aug 18.

Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Australia.

Vancomycin-resistant (VREfm) is an emerging antibiotic-resistant pathogen. Strain-level investigations are beginning to reveal the molecular mechanisms used by VREfm to colonize regions of the human bowel. However, the role of commensal bacteria during VREfm colonization, in particular following antibiotic treatment, remains largely unknown. We employed amplicon 16S rRNA gene sequencing and metabolomics in a murine model system to try and investigate functional roles of the gut microbiome during VREfm colonization. First-order taxonomic shifts between and within the gut microbial community composition were detected both in response to pretreatment using ceftriaxone and to subsequent VREfm challenge. Using neural networking approaches to find cooccurrence profiles of bacteria and metabolites, we detected key metabolome features associated with butyric acid during and after VREfm colonization. These metabolite features were associated with , indicative of a transition toward a preantibiotic naive microbiome. This study shows the impacts of antibiotics on the gut ecosystem and the progression of the microbiome in response to colonization with VREfm. Our results offer insights toward identifying potential nonantibiotic alternatives to eliminate VREfm through metabolic reengineering to preferentially select for This study demonstrates the importance and power of linking bacterial composition profiling with metabolomics to find the interactions between commensal gut bacteria and a specific pathogen. Knowledge from this research will inform gut microbiome engineering strategies, with the aim of translating observations from animal models to human-relevant therapeutic applications.
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http://dx.doi.org/10.1128/mSystems.00452-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7438022PMC
August 2020

Structure-Activity Relationships of Daptomycin Lipopeptides.

J Med Chem 2020 11 6;63(22):13266-13290. Epub 2020 Aug 6.

Department of Pharmacology & Therapeutics, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, VIC 3010, Australia.

Daptomycin is a calcium-dependent cyclic lipodepsipeptide derived from the soil saprotroph , and its antibiotic properties make it a key agent for treatment of drug-resistant Gram-positive infections. It is most commonly used clinically for the treatment of Gram-positive skin and skin structure infections (SSSI), bacteremia, and right-sided endocarditis infections associated with , including methicillin resistant (MRSA). It has also been used "off-label" for Enterococcal infections. There has been a tremendous amount of research investigating its mode of action, resistance mechanisms, and biosynthesis of this clinically important antimicrobial agent. Although we cover the latter aspects in detail, the primary focus of this review is to provide the most comprehensive and up-to-date reference for the medicinal chemist on the structure-activity-toxicity of this important class of lipopeptide antibiotics.
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http://dx.doi.org/10.1021/acs.jmedchem.0c00780DOI Listing
November 2020

Biphasic Outbreak of Invasive Group A Streptococcus Disease in Eldercare Facility, New Zealand.

Emerg Infect Dis 2020 05;26(5):841-848

A 3-month outbreak of invasive group A Streptococcus disease at an eldercare facility, in which 5 persons died, was biphasic. Although targeted chemoprophylaxis contained the initial outbreak, a second phase of the outbreak occurred after infection control processes ended. To retrospectively investigate the genomic epidemiology of the biphasic outbreak, we used whole-genome sequencing and multiple bioinformatics approaches. Analysis of isolates from the outbreak and isolates prospectively collected during the outbreak response indicated a single S. pyogenes emm81 clone among residents and staff members. Outbreak isolates differed from nonoutbreak emm81 isolates by harboring an integrative conjugative genomic element that contained the macrolide resistance determinant erm(TR). This study shows how retrospective high-resolution genomic investigations identified rapid spread of a closed-facilty clonal outbreak that was controlled, but not readily cleared, by infection control management procedures.
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http://dx.doi.org/10.3201/eid2605.190131DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7181915PMC
May 2020

Mining the Methylome Reveals Extensive Diversity in Staphylococcus epidermidis Restriction Modification.

mBio 2019 12 17;10(6). Epub 2019 Dec 17.

Department of Microbiology and Immunology, The University of Melbourne at The Doherty Institute for Infection and Immunity, Victoria, Australia

is a significant opportunistic pathogen of humans. Molecular studies in this species have been hampered by the presence of restriction-modification (RM) systems that limit introduction of foreign DNA. Here, we establish the complete genomes and methylomes for seven clinically significant, genetically diverse isolates and perform the first systematic genomic analyses of the type I RM systems within both and Our analyses revealed marked differences in the gene arrangement, chromosomal location, and movement of type I RM systems between the two species. Unlike , type I RM systems demonstrate extensive diversity even within a single genetic lineage. This is contrary to current assumptions and has important implications for approaching the genetic manipulation of Using plasmid artificial modification (PAM) to express , we readily overcame restriction barriers in and achieved electroporation efficiencies equivalent to those of modification-deficient mutants. With these functional experiments, we demonstrated how genomic data can be used to predict both the functionality of type I RM systems and the potential for a strain to be electroporation proficient. We outline an efficient approach for the genetic manipulation of strains from diverse genetic backgrounds, including those that have hitherto been intractable. Additionally, we identified BPH0736, a naturally restriction-defective, clinically significant, multidrug-resistant ST2 isolate, as an ideal candidate for molecular studies. is a major cause of hospital-acquired infections, especially those related to implanted medical devices. Understanding how causes disease and devising ways to combat these infections have been hindered by an inability to genetically manipulate clinically significant hospital-adapted strains. Here, we provide the first comprehensive analyses of the barriers to the uptake of foreign DNA in and demonstrate that these are distinct from those described for Using these insights, we demonstrate an efficient approach for the genetic manipulation of to enable the study of clinical isolates for the first time.
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http://dx.doi.org/10.1128/mBio.02451-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6918075PMC
December 2019

Genomic Analysis of Fluoroquinolone- and Tetracycline-Resistant Campylobacter jejuni Sequence Type 6964 in Humans and Poultry, New Zealand, 2014-2016.

Emerg Infect Dis 2019 12;25(12):2226-2234

In 2014, antimicrobial drug-resistant Campylobacter jejuni sequence type 6964 emerged contemporaneously in poultry from 3 supply companies in the North Island of New Zealand and as a major cause of campylobacteriosis in humans in New Zealand. This lineage, not previously identified in New Zealand, was resistant to tetracycline and fluoroquinolones. Genomic analysis revealed divergence into 2 major clades; both clades were associated with human infection, 1 with poultry companies A and B and the other with company C. Accessory genome evolution was associated with a plasmid, phage insertions, and natural transformation. We hypothesize that the tetO gene and a phage were inserted into the chromosome after conjugation, leaving a remnant plasmid that was lost from isolates from company C. The emergence and rapid spread of a resistant clone of C. jejuni in New Zealand, coupled with evolutionary change in the accessory genome, demonstrate the need for ongoing Campylobacter surveillance among poultry and humans.
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http://dx.doi.org/10.3201/eid2512.190267DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6874264PMC
December 2019

Unstable chromosome rearrangements in cause phenotype switching associated with persistent infections.

Proc Natl Acad Sci U S A 2019 10 16;116(40):20135-20140. Epub 2019 Sep 16.

Department of Microbiology and Immunology, The University of Melbourne, The Peter Doherty Institute for Infection and Immunity, Melbourne, 3000, Australia;

small-colony variants (SCVs) are associated with unusually chronic and persistent infections despite active antibiotic treatment. The molecular basis for this clinically important phenomenon is poorly understood, hampered by the instability of the SCV phenotype. Here we investigated the genetic basis for an unstable SCV that arose spontaneously while studying rifampicin resistance. This SCV showed no nucleotide differences across its genome compared with a normal-colony variant (NCV) revertant, yet the SCV presented the hallmarks of linked to persistent infection: down-regulation of virulence genes and reduced hemolysis and neutrophil chemotaxis, while exhibiting increased survival in blood and ability to invade host cells. Further genome analysis revealed chromosome structural variation uniquely associated with the SCV. These variations included an asymmetric inversion across half of the chromosome via recombination between type I restriction modification system (T1RMS) genes, and the activation of a conserved prophage harboring the immune evasion cluster (IEC). Phenotypic reversion to the wild-type-like NCV state correlated with reversal of the chromosomal inversion (CI) and with prophage stabilization. Further analysis of 29 complete genomes showed strong signatures of recombination between genes, suggesting that analogous CI has repeatedly occurred during evolution. Using qPCR and long-read amplicon deep sequencing, we detected subpopulations with T1RMS rearrangements causing CIs and prophage activation across major lineages. Here, we have discovered a previously unrecognized and widespread mechanism of reversible genomic instability in associated with SCV generation and persistent infections.
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http://dx.doi.org/10.1073/pnas.1904861116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6778178PMC
October 2019

Isolated From New Zealand Mussels Harbor a Putative Virulence Plasmid.

Front Microbiol 2019 5;10:1802. Epub 2019 Aug 5.

Doherty Applied Microbial Genomics, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC, Australia.

A wide range of species have been described from shellfish in various countries but their presence has not been investigated in Australasia, in which shellfish are a popular delicacy. Since several arcobacters are considered to be emerging pathogens, we undertook a small study to evaluate their presence in several different shellfish, including greenshell mussels, oysters, and abalone (paua) in New Zealand. , a species associated with human gastroenteritis, was the only species isolated, from greenshell mussels. Whole-genome sequencing revealed a range of genomic traits in these strains that were known or associated virulence factors. Furthermore, we describe the first putative virulence plasmid in , containing lytic, immunoavoidance, adhesion, antibiotic resistance, and gene transfer traits, among others. Complete genome sequence determination using a combination of long- and short-read genome sequencing strategies, was needed to identify the plasmid, clearly identifying its benefits. The potential for plasmids to disseminate virulence traits among and other species warrants further consideration by researchers interested in the risks to public health from these organisms.
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http://dx.doi.org/10.3389/fmicb.2019.01802DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6690266PMC
August 2019

Agricultural Origins of a Highly Persistent Lineage of Vancomycin-Resistant in New Zealand.

Appl Environ Microbiol 2019 07 17;85(13). Epub 2019 Jun 17.

Department of Microbiology and Immunology, University of Otago, Dunedin, New Zealand

and are human and animal gut commensals. Vancomycin-resistant enterococci (VRE) are important opportunistic pathogens with limited treatment options. Historically, the glycopeptide antibiotics vancomycin and avoparcin selected for the emergence of vancomycin resistance in human and animal isolates, respectively, resulting in global cessation of avoparcin use between 1997 and 2000. To better understand human- and animal-associated VRE strains in the postavoparcin era, we sequenced the genomes of 231 VRE isolates from New Zealand (NZ; 75 human clinical, 156 poultry) cultured between 1998 and 2009. lineages and their antibiotic resistance carriage patterns strictly delineated between agricultural and human reservoirs, with bacitracin resistance ubiquitous in poultry but absent in clinical strains. In contrast, one lineage (ST108) predominated in both poultry and human isolates in the 3 years following avoparcin discontinuation. Both phylogenetic and antimicrobial susceptibility (i.e., ubiquitous bacitracin resistance in both poultry and clinical ST108 isolates) analyses suggest an agricultural origin for the ST108 lineage. VRE isolate resistomes were carried on multiple, heterogeneous plasmids. In some isolate genomes, bacitracin, erythromycin, and vancomycin resistance elements were colocalized, indicating multiple potentially linked selection mechanisms. Historical antimicrobial use in NZ agriculture has driven the evolution of ST108, a VRE lineage carrying a range of clinically relevant antimicrobial resistances. The persistence of this lineage in NZ for over a decade indicates that coselection may be an important stabilizing mechanism for its persistence.
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http://dx.doi.org/10.1128/AEM.00137-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6581176PMC
July 2019

Remodeling of pSK1 Family Plasmids and Enhanced Chlorhexidine Tolerance in a Dominant Hospital Lineage of Methicillin-Resistant .

Antimicrob Agents Chemother 2019 05 25;63(5). Epub 2019 Apr 25.

Department of Microbiology & Immunology, The University of Melbourne at The Peter Doherty Institute for Infection & Immunity, Melbourne, Victoria, Australia.

is a significant human pathogen whose evolution and adaptation have been shaped in part by mobile genetic elements (MGEs), facilitating the global spread of extensive antimicrobial resistance. However, our understanding of the evolutionary dynamics surrounding MGEs, in particular, how changes in the structure of multidrug resistance (MDR) plasmids may influence important staphylococcal phenotypes, is incomplete. Here, we undertook a population and functional genomics study of 212 methicillin-resistant (MRSA) sequence type 239 (ST239) isolates collected over 32 years to explore the evolution of the pSK1 family of MDR plasmids, illustrating how these plasmids have coevolved with and contributed to the successful adaptation of this persistent MRSA lineage. Using complete genomes and temporal phylogenomics, we reconstructed the evolution of the pSK1 family lineage from its emergence in the late 1970s and found that multiple structural variants have arisen. Plasmid maintenance and stability were linked to IS- and IS-mediated chromosomal integration and disruption of the plasmid replication machinery. Overlaying genomic comparisons with phenotypic susceptibility data for gentamicin, trimethoprim, and chlorhexidine, it appeared that pSK1 has contributed to enhanced resistance in ST239 MRSA isolates through two mechanisms: (i) acquisition of plasmid-borne resistance mechanisms increasing the rates of gentamicin resistance and reduced chlorhexidine susceptibility and (ii) changes in the plasmid configuration linked with further enhancement of chlorhexidine tolerance. While the exact mechanism of enhanced tolerance remains elusive, this research has uncovered a potential evolutionary response of ST239 MRSA to biocides, one of which may contribute to the ongoing persistence and adaptation of this lineage within health care institutions.
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http://dx.doi.org/10.1128/AAC.02356-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6496109PMC
May 2019

Reconstruction of the Genomes of Drug-Resistant Pathogens for Outbreak Investigation through Metagenomic Sequencing.

mSphere 2019 01 16;4(1). Epub 2019 Jan 16.

Microbiological Diagnostic Unit Public Health Laboratory, Department of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Victoria, Australia

Culture-independent methods that target genome fragments have shown promise in identifying certain pathogens, but the holy grail of comprehensive pathogen genome detection from microbiologically complex samples for subsequent forensic analyses remains a challenge. In the context of an investigation of a nosocomial outbreak, we used shotgun metagenomic sequencing of a human fecal sample and a neural network algorithm based on tetranucleotide frequency profiling to reconstruct microbial genomes and tested the same approach using rectal swabs from a second patient. The approach rapidly and readily detected the genome of carbapenemase (KPC)-producing in the patient fecal specimen and in the rectal swab sample, achieving a level of strain resolution that was sufficient for confident transmission inference during a highly clonal outbreak. The analysis also detected previously unrecognized colonization of the patient by vancomycin-resistant , another multidrug-resistant bacterium. The study results reported here perfectly demonstrate the power and promise of clinical metagenomics to recover genome sequences of important drug-resistant bacteria and to rapidly provide rich data that inform outbreak investigations and treatment decisions, independently of the need to culture the organisms.
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http://dx.doi.org/10.1128/mSphere.00529-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6336080PMC
January 2019

Co-circulation of Multidrug-resistant Shigella Among Men Who Have Sex With Men in Australia.

Clin Infect Dis 2019 10;69(9):1535-1544

Microbiological Diagnostic Unit Public Health Laboratory, Department of Microbiology and Immunology, The University of Melbourne at The Peter Doherty Institute for Infection and Immunity, Melbourne.

Background: In urban Australia, the burden of shigellosis is either in returning travelers from shigellosis-endemic regions or in men who have sex with men (MSM). Here, we combine genomic data with comprehensive epidemiological data on sexual exposure and travel to describe the spread of multidrug-resistant Shigella lineages.

Methods: A population-level study of all cultured Shigella isolates in the state of Victoria, Australia, was undertaken from 1 January 2016 through 31 March 2018. Antimicrobial susceptibility testing, whole-genome sequencing, and bioinformatic analyses of 545 Shigella isolates were performed at the Microbiological Diagnostic Unit Public Health Laboratory. Risk factor data on travel and sexual exposure were collected through enhanced surveillance forms or by interviews.

Results: Rates of antimicrobial resistance were high, with 17.6% (95/541) and 50.6% (274/541) resistance to ciprofloxacin and azithromycin, respectively. There were strong associations between antimicrobial resistance, phylogeny, and epidemiology. Specifically, 2 major MSM-associated lineages were identified: a Shigellasonnei lineage (n = 159) and a Shigella flexneri 2a lineage (n = 105). Of concern, 147/159 (92.4%) of isolates within the S. sonnei MSM-associated lineage harbored mutations associated with reduced susceptibility to recommended oral antimicrobials: namely, azithromycin, trimethoprim-sulfamethoxazole, and ciprofloxacin. Long-read sequencing demonstrated global dissemination of multidrug-resistant plasmids across Shigella species and lineages, but predominantly associated with MSM isolates.

Conclusions: Our contemporary data highlight the ongoing public health threat posed by resistant Shigella, both in Australia and globally. Urgent multidisciplinary public health measures are required to interrupt transmission and prevent infection.
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http://dx.doi.org/10.1093/cid/ciz005DOI Listing
October 2019

Burkholderia lata Infections from Intrinsically Contaminated Chlorhexidine Mouthwash, Australia, 2016.

Emerg Infect Dis 2018 11;24(11):2109-2111

Burkholderia lata was isolated from 8 intensive care patients at 2 tertiary hospitals in Australia. Whole-genome sequencing demonstrated that clinical and environmental isolates originated from a batch of contaminated commercial chlorhexidine mouthwash. Genomic analysis identified efflux pump-encoding genes as potential facilitators of bacterial persistence within this biocide.
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http://dx.doi.org/10.3201/eid2411.171929DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6199994PMC
November 2018

The changing landscape of vancomycin-resistant Enterococcus faecium in Australia: a population-level genomic study.

J Antimicrob Chemother 2018 12;73(12):3268-3278

The Microbiological Diagnostic Unit Public Health Laboratory, Department of Microbiology and Immunology, The University of Melbourne, at The Peter Doherty Institute for Infection and Immunity, 792 Elizabeth Street, Level 1, Melbourne, Victoria, Australia.

Background: Vancomycin-resistant Enterococcus faecium (VREfm) represent a major source of nosocomial infection worldwide. In Australia, there has been a recent concerning increase in bacteraemia associated with the vanA genotype, prompting investigation into the genomic epidemiology of VREfm.

Methods: A population-level study of VREfm (10 November-9 December 2015) was conducted. A total of 321 VREfm isolates (from 286 patients) across Victoria State were collected and sequenced with Illumina NextSeq. SNPs were used to assess relatedness. STs and genes associated with resistance and virulence were identified. The vanA-harbouring plasmid from an isolate from each ST was assembled using long-read data. Illumina reads from remaining isolates were then mapped to these assemblies to identify their probable vanA-harbouring plasmid.

Results: vanA-VREfm comprised 17.8% of isolates. ST203, ST80 and a pstS(-) clade, ST1421, predominated (30.5%, 30.5% and 37.2%, respectively). Most vanB-VREfm were ST796 (77.7%). vanA-VREfm were more closely related within hospitals versus between them [core SNPs 10 (IQR 1-357) versus 356 (179-416), respectively], suggesting discrete introductions of vanA-VREfm, with subsequent intra-hospital transmission. In contrast, vanB-VREfm had similar core SNP distributions within versus between hospitals, due to widespread dissemination of ST796. Different vanA-harbouring plasmids were found across STs. With the exception of ST78 and ST796, Tn1546 transposons also varied. Phylogenetic analysis revealed Australian strains were often interspersed with those from other countries, suggesting ongoing cross-continental transmission.

Conclusions: Emerging vanA-VREfm in Australia is polyclonal, indicating repeat introductions of vanA-VREfm into hospitals and subsequent dissemination. The close relationship to global strains reinforces the need for ongoing screening and control of VREfm in Australia and abroad.
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http://dx.doi.org/10.1093/jac/dky331DOI Listing
December 2018

Genomic Analysis of Multiresistant Staphylococcus capitis Associated with Neonatal Sepsis.

Antimicrob Agents Chemother 2018 11 24;62(11). Epub 2018 Oct 24.

Department of Microbiology and Immunology, Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, Australia

Coagulase-negative staphylococci (CoNS), such as , are major causes of bloodstream infections in neonatal intensive care units (NICUs). Recently, a distinct clone of (designated NRCS-A) has emerged as an important pathogen in NICUs internationally. Here, 122 isolates from New Zealand (NZ) underwent whole-genome sequencing (WGS), and these data were supplemented with publicly available sequence reads. Phylogenetic and comparative genomic analyses were performed, as were phenotypic assessments of antimicrobial resistance, biofilm formation, and plasmid segregational stability on representative isolates. A distinct lineage of was identified in NZ associated with neonates and the NICU environment. Isolates from this lineage produced increased levels of biofilm, displayed higher levels of tolerance to chlorhexidine, and were multidrug resistant. Although similar to globally circulating NICU-associated strains at a core-genome level, NZ NICU isolates carried a novel stably maintained multidrug-resistant plasmid that was not present in non-NICU isolates. Neonatal blood culture isolates were indistinguishable from environmental isolates found on fomites, such as stethoscopes and neonatal incubators, but were generally distinct from those isolates carried by NICU staff. This work implicates the NICU environment as a potential reservoir for neonatal sepsis caused by and highlights the capacity of genomics-based tracking and surveillance to inform future hospital infection control practices aimed at containing the spread of this important neonatal pathogen.
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http://dx.doi.org/10.1128/AAC.00898-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6201123PMC
November 2018

Increasing tolerance of hospital to handwash alcohols.

Sci Transl Med 2018 08;10(452)

Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Victoria 3010, Australia.

Alcohol-based disinfectants and particularly hand rubs are a key way to control hospital infections worldwide. Such disinfectants restrict transmission of pathogens, such as multidrug-resistant and Despite this success, health care infections caused by are increasing. We tested alcohol tolerance of 139 hospital isolates of obtained between 1997 and 2015 and found that isolates after 2010 were 10-fold more tolerant to killing by alcohol than were older isolates. Using a mouse gut colonization model of transmission, we showed that alcohol-tolerant resisted standard 70% isopropanol surface disinfection, resulting in greater mouse gut colonization compared to alcohol-sensitive We next looked for bacterial genomic signatures of adaptation. Alcohol-tolerant accumulated mutations in genes involved in carbohydrate uptake and metabolism. Mutagenesis confirmed the roles of these genes in the tolerance of to isopropanol. These findings suggest that bacterial adaptation is complicating infection control recommendations, necessitating additional procedures to prevent from spreading in hospital settings.
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http://dx.doi.org/10.1126/scitranslmed.aar6115DOI Listing
August 2018

Seven Salmonella Typhimurium Outbreaks in Australia Linked by Trace-Back and Whole Genome Sequencing.

Foodborne Pathog Dis 2018 05 20;15(5):285-292. Epub 2018 Mar 20.

1 National Centre for Epidemiology and Population Health, Research School of Population Health, The Australian National University , Canberra, Australia .

Salmonella Typhimurium is a common cause of foodborne illness in Australia. We report on seven outbreaks of Salmonella Typhimurium multilocus variable-number tandem-repeat analysis (MLVA) 03-26-13-08-523 (European convention 2-24-12-7-0212) in three Australian states and territories investigated between November 2015 and March 2016. We identified a common egg grading facility in five of the outbreaks. While no Salmonella Typhimurium was detected at the grading facility and eggs could not be traced back to a particular farm, whole genome sequencing (WGS) of isolates from cases from all seven outbreaks indicated a common source. WGS was able to provide higher discriminatory power than MLVA and will likely link more Salmonella Typhimurium cases between states and territories in the future. National harmonization of Salmonella surveillance is important for effective implementation of WGS for Salmonella outbreak investigations.
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http://dx.doi.org/10.1089/fpd.2017.2353DOI Listing
May 2018

Genome-by-genome approach for fast bacterial genealogical relationship evaluation.

Bioinformatics 2018 09;34(17):3025-3027

mEpiLab, New Zealand Food Safety Science & Research Centre, Institute of Veterinary, Animal and Biomedical Sciences, Massey University, Palmerston North, New Zealand.

Motivation: Large-scale whole-genome sequencing dataset-based studies are becoming increasingly common in pathogen surveillance and outbreak investigations. A highly discriminative and time-efficient bioinformatics tool is needed to transform large amounts of sequencing data into usable biological information. To replace the intuitive, yet inefficient, way of gene-by-gene allele calling algorithm, a new algorithm using genome-by-genome approach was developed.

Results: Tests showed that the program equipped with the new algorithm achieved significant improvements in allele calling efficiency compared to a conventional gene-by-gene approach. The new program, Fast-GeP, rendered a fast and easy way to infer high-resolution genealogical relationships between bacterial isolates using whole-genome sequencing data.

Availability And Implementation: FAST-GeP is freely available from: https://github.com/jizhang-nz/fast-GeP.

Supplementary Information: Supplementary data are available at Bioinformatics online.
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http://dx.doi.org/10.1093/bioinformatics/bty195DOI Listing
September 2018

1,2,4-Oxadiazole antimicrobials act synergistically with daptomycin and display rapid kill kinetics against MDR Enterococcus faecium.

J Antimicrob Chemother 2018 06;73(6):1562-1569

Antimicrobial Reference and Research Unit, Microbiological Diagnostic Unit Public Health Laboratory, Department of Microbiology & Immunology, Doherty Institute, The University of Melbourne, Melbourne, Australia.

Background: Enterococcus faecium is an important nosocomial pathogen. It has a high propensity for horizontal gene transfer, which has resulted in the emergence of MDR strains that are difficult to treat. The most notorious of these, vancomycin-resistant E. faecium, are usually treated with linezolid or daptomycin. Resistance has, however, been reported, meaning that new therapeutics are urgently needed. The 1,2,4-oxadiazoles are a recently discovered family of antimicrobials that are active against Gram-positive pathogens and therefore have therapeutic potential for treating E. faecium. However, only limited data are available on the activity of these antimicrobials against E. faecium.

Objectives: To determine whether the 1,2,4-oxadiazole antimicrobials are active against MDR and daptomycin-non-susceptible E. faecium.

Methods: The activity of the 1,2,4-oxadiazole antimicrobials against vancomycin-susceptible, vancomycin-resistant and daptomycin-non-susceptible E. faecium was determined using susceptibility testing, time-kill assays and synergy assays. Toxicity was also evaluated against human cells by XTT and haemolysis assays.

Results: The 1,2,4-oxadiazoles are active against a range of MDR E. faecium, including isolates that display non-susceptibility to vancomycin and daptomycin. This class of antimicrobial displays rapid bactericidal activity and demonstrates superior killing of E. faecium compared with daptomycin. Finally, the 1,2,4-oxadiazoles act synergistically with daptomycin against E. faecium, with subinhibitory concentrations reducing the MIC of daptomycin for non-susceptible isolates to a level below the clinical breakpoint.

Conclusions: The 1,2,4-oxadiazoles are active against MDR and daptomycin-non-susceptible E. faecium and hold great promise as future therapeutics for treating infections caused by these difficult-to-treat isolates.
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http://dx.doi.org/10.1093/jac/dky064DOI Listing
June 2018

Complete Genome Sequence of a New Zealand Isolate of the Bovine Pathogen Streptococcus uberis.

Genome Announc 2018 Mar 1;6(9). Epub 2018 Mar 1.

Centre for Integrative Microbial Evolution (CIME), Faculty of Mathematics and Natural Sciences, University of Oslo, Oslo, Norway.

forms part of the native microbiota of cattle and is able to opportunistically infect the mammary gland; as such, it is a leading cause of bovine mastitis globally. Here, we report the complete genome sequence of NZ01, isolated in New Zealand from a cow with a clinical case of bovine mastitis.
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http://dx.doi.org/10.1128/genomeA.00119-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5834334PMC
March 2018

Incorporating Whole-Genome Sequencing into Public Health Surveillance: Lessons from Prospective Sequencing of Salmonella Typhimurium in Australia.

Foodborne Pathog Dis 2018 03 16;15(3):161-167. Epub 2018 Jan 16.

1 National Centre for Epidemiology and Population Health, Research School of Population Health, The Australian National University , Canberra, Australia .

In Australia, the incidence of Salmonella Typhimurium has increased dramatically over the past decade. Whole-genome sequencing (WGS) is transforming public health microbiology, but poses challenges for surveillance. To compare WGS-based approaches with conventional typing for Salmonella surveillance, we performed concurrent WGS and multilocus variable-number tandem-repeat analysis (MLVA) of Salmonella Typhimurium isolates from the Australian Capital Territory (ACT) for a period of 5 months. We exchanged data via a central shared virtual machine and performed comparative genomic analyses. Epidemiological evidence was integrated with WGS-derived data to identify related isolates and sources of infection, and we compared WGS data for surveillance with findings from MLVA typing. We found that WGS data combined with epidemiological data linked an additional 9% of isolates to at least one other isolate in the study in contrast to MLVA and epidemiological data, and 19% more isolates than epidemiological data alone. Analysis of risk factors showed that in one WGS-defined cluster, human cases had higher odds of purchasing a single egg brand. While WGS was more sensitive and specific than conventional typing methods, we identified barriers to uptake of genomic surveillance around complexity of reporting of WGS results, timeliness, acceptability, and stability. In conclusion, WGS offers higher resolution of Salmonella Typhimurium laboratory surveillance than existing methods and can provide further evidence on sources of infection in case and outbreak investigations for public health action. However, there are several challenges that need to be addressed for effective implementation of genomic surveillance in Australia.
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http://dx.doi.org/10.1089/fpd.2017.2352DOI Listing
March 2018

Translating genomics into practice for real-time surveillance and response to carbapenemase-producing Enterobacteriaceae: evidence from a complex multi-institutional KPC outbreak.

PeerJ 2018 3;6:e4210. Epub 2018 Jan 3.

Doherty Applied Microbial Genomics, The University of Melbourne at The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia.

Background: Until recently, carbapenemase (KPC)-producing Enterobacteriaceae were rarely identified in Australia. Following an increase in the number of incident cases across the state of Victoria, we undertook a real-time combined genomic and epidemiological investigation. The scope of this study included identifying risk factors and routes of transmission, and investigating the utility of genomics to enhance traditional field epidemiology for informing management of established widespread outbreaks.

Methods: All KPC-producing Enterobacteriaceae isolates referred to the state reference laboratory from 2012 onwards were included. Whole-genome sequencing was performed in parallel with a detailed descriptive epidemiological investigation of each case, using Illumina sequencing on each isolate. This was complemented with PacBio long-read sequencing on selected isolates to establish high-quality reference sequences and interrogate characteristics of KPC-encoding plasmids.

Results: Initial investigations indicated that the outbreak was widespread, with 86 KPC-producing Enterobacteriaceae isolates ( 92%) identified from 35 different locations across metropolitan and rural Victoria between 2012 and 2015. Initial combined analyses of the epidemiological and genomic data resolved the outbreak into distinct nosocomial transmission networks, and identified healthcare facilities at the epicentre of KPC transmission. New cases were assigned to transmission networks in real-time, allowing focussed infection control efforts. PacBio sequencing confirmed a secondary transmission network arising from inter-species plasmid transmission. Insights from Bayesian transmission inference and analyses of within-host diversity informed the development of state-wide public health and infection control guidelines, including interventions such as an intensive approach to screening contacts following new case detection to minimise unrecognised colonisation.

Conclusion: A real-time combined epidemiological and genomic investigation proved critical to identifying and defining multiple transmission networks of KPC Enterobacteriaceae, while data from either investigation alone were inconclusive. The investigation was fundamental to informing infection control measures in real-time and the development of state-wide public health guidelines on carbapenemase-producing Enterobacteriaceae surveillance and management.
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http://dx.doi.org/10.7717/peerj.4210DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5756455PMC
January 2018

Topical Antibiotic Use Coselects for the Carriage of Mobile Genetic Elements Conferring Resistance to Unrelated Antimicrobials in Staphylococcus aureus.

Antimicrob Agents Chemother 2018 02 25;62(2). Epub 2018 Jan 25.

Department of Microbiology & Immunology, Doherty Institute, The University of Melbourne, Melbourne, Australia

Topical antibiotics, such as mupirocin and fusidic acid, are commonly used in the prevention and treatment of skin infections, particularly those caused by staphylococci. However, the widespread use of these agents is associated with increased resistance to these agents, potentially limiting their efficacy. Of particular concern is the observation that resistance to topical antibiotics is often associated with multidrug resistance, suggesting that topical antibiotics may play a role in the emergence of multidrug-resistant (MDR) strains. New Zealand (NZ) has some of the highest globally recorded rates of topical antibiotic usage and resistance. Using a combination of Pacific Biosciences single-molecule real-time (SMRT) whole-genome sequencing, Illumina short-read sequencing, and Bayesian phylogenomic modeling on 118 new multilocus sequence type 1 (ST1) community isolates from New Zealand and 61 publically available international ST1 genome sequences, we demonstrate a strong correlation between the clinical introduction of topical antibiotics and the emergence of MDR ST1 We also provide experimental evidence showing that exposure to topical antibiotics can lead to the rapid selection of MDR isolates carrying plasmids that confer resistance to multiple unrelated antibiotics, from within a mixed population of competitor strains. These findings have important implications regarding the impact of the indiscriminate use of topical antibiotics.
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http://dx.doi.org/10.1128/AAC.02000-17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5786761PMC
February 2018

Genomic epidemiology and antimicrobial resistance of Neisseria gonorrhoeae in New Zealand.

J Antimicrob Chemother 2018 02;73(2):353-364

Doherty Applied Microbial Genomics, Department of Microbiology and Immunology, The University of Melbourne, The Peter Doherty Institute for Infection and Immunity, 792 Elizabeth Street, Level 1, Melbourne, Victoria 3000, Australia.

Background: Antimicrobial-resistant Neisseria gonorrhoeae is a major threat to public health. No studies to date have examined the genomic epidemiology of gonorrhoea in the Western Pacific Region, where the incidence of gonorrhoea is particularly high.

Methods: A population-level study of N. gonorrhoeae in New Zealand (October 2014 to May 2015). Comprehensive susceptibility testing and WGS data were obtained for 398 isolates. Relatedness was inferred using phylogenetic trees, and pairwise core SNPs. Mutations and genes known to be associated with resistance were identified, and correlated with phenotype.

Results: Eleven clusters were identified. In six of these clusters, >25% of isolates were from females, while in eight of them, >15% of isolates were from females. Drug resistance was common; 98%, 32% and 68% of isolates were non-susceptible to penicillin, ciprofloxacin and tetracycline, respectively. Elevated MICs to extended-spectrum cephalosporins (ESCs) were observed in 3.5% of isolates (cefixime MICs ≥ 0.12 mg/L, ceftriaxone MICs ≥ 0.06 mg/L). Only nine isolates had penA XXXIV genotypes, three of which had decreased susceptibility to ESCs (MIC = 0.12 mg/L). Azithromycin non-susceptibility was identified in 43 isolates (10.8%); two of these isolates had 23S mutations (C2611T, 4/4 alleles), while all had mutations in mtrR or its promoter.

Conclusions: The high proportion of females in clusters suggests transmission is not exclusively among MSM in New Zealand; re-assessment of risk factors for transmission may be warranted in this context. As elevated MICs of ESCs and/or azithromycin were found in closely related strains, targeted public health interventions to halt transmission are urgently needed.
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http://dx.doi.org/10.1093/jac/dkx405DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5890773PMC
February 2018

A Supervised Statistical Learning Approach for Accurate Legionella pneumophila Source Attribution during Outbreaks.

Appl Environ Microbiol 2017 11 17;83(21). Epub 2017 Oct 17.

Department of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Parkville, Victoria, Australia

Public health agencies are increasingly relying on genomics during Legionnaires' disease investigations. However, the causative bacterium () has an unusual population structure, with extreme temporal and spatial genome sequence conservation. Furthermore, Legionnaires' disease outbreaks can be caused by multiple genotypes in a single source. These factors can confound cluster identification using standard phylogenomic methods. Here, we show that a statistical learning approach based on core genome single nucleotide polymorphism (SNP) comparisons eliminates ambiguity for defining outbreak clusters and accurately predicts exposure sources for clinical cases. We illustrate the performance of our method by genome comparisons of 234 isolates obtained from patients and cooling towers in Melbourne, Australia, between 1994 and 2014. This collection included one of the largest reported Legionnaires' disease outbreaks, which involved 125 cases at an aquarium. Using only sequence data from cooling tower isolates and including all core genome variation, we built a multivariate model using discriminant analysis of principal components (DAPC) to find cooling tower-specific genomic signatures and then used it to predict the origin of clinical isolates. Model assignments were 93% congruent with epidemiological data, including the aquarium Legionnaires' disease outbreak and three other unrelated outbreak investigations. We applied the same approach to a recently described investigation of Legionnaires' disease within a UK hospital and observed a model predictive ability of 86%. We have developed a promising means to breach genetic diversity extremes and provide objective source attribution data for outbreak investigations. Microbial outbreak investigations are moving to a paradigm where whole-genome sequencing and phylogenetic trees are used to support epidemiological investigations. It is critical that outbreak source predictions are accurate, particularly for pathogens, like , which can spread widely and rapidly via cooling system aerosols, causing Legionnaires' disease. Here, by studying hundreds of genomes collected over 21 years around a major Australian city, we uncovered limitations with the phylogenetic approach that could lead to a misidentification of outbreak sources. We implement instead a statistical learning technique that eliminates the ambiguity of inferring disease transmission from phylogenies. Our approach takes geolocation information and core genome variation from environmental isolates to build statistical models that predict with high confidence the environmental source of clinical during disease outbreaks. We show the versatility of the technique by applying it to unrelated Legionnaires' disease outbreaks in Australia and the UK.
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http://dx.doi.org/10.1128/AEM.01482-17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5648911PMC
November 2017

Current and Emerging Topical Antibacterials and Antiseptics: Agents, Action, and Resistance Patterns.

Clin Microbiol Rev 2017 07;30(3):827-860

Microbiological Diagnostic Unit Public Health Laboratory, Department of Microbiology & Immunology, The University of Melbourne at The Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia.

Bacterial skin infections represent some of the most common infectious diseases globally. Prevention and treatment of skin infections can involve application of a topical antimicrobial, which may be an antibiotic (such as mupirocin or fusidic acid) or an antiseptic (such as chlorhexidine or alcohol). However, there is limited evidence to support the widespread prophylactic or therapeutic use of topical agents. Challenges involved in the use of topical antimicrobials include increasing rates of bacterial resistance, local hypersensitivity reactions (particularly to older agents, such as bacitracin), and concerns about the indiscriminate use of antiseptics potentially coselecting for antibiotic resistance. We review the evidence for the major clinical uses of topical antibiotics and antiseptics. In addition, we review the mechanisms of action of common topical agents and define the clinical and molecular epidemiology of antimicrobial resistance in these agents. Moreover, we review the potential use of newer and emerging agents, such as retapamulin and ebselen, and discuss the role of antiseptic agents in preventing bacterial skin infections. A comprehensive understanding of the clinical efficacy and drivers of resistance to topical agents will inform the optimal use of these agents to preserve their activity in the future.
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http://dx.doi.org/10.1128/CMR.00112-16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5475228PMC
July 2017

Target-Specific Assay for Rapid and Quantitative Detection of Mycobacterium chimaera DNA.

J Clin Microbiol 2017 06 5;55(6):1847-1856. Epub 2017 Apr 5.

Department of Microbiology and Immunology, The Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Victoria, Australia

is an opportunistic environmental mycobacterium belonging to the - complex. Although most commonly associated with pulmonary disease, there has been growing awareness of invasive infections following cardiac surgery. Investigations suggest worldwide spread of a specific clone, associated with contaminated hospital heater-cooler units used during the surgery. Given the global dissemination of this clone, its potential to cause invasive disease, and the laboriousness of current culture-based diagnostic methods, there is a pressing need to develop rapid and accurate diagnostic assays specific for Here, we assessed 354 mycobacterial genome sequences and confirmed that is a phylogenetically coherent group. comparisons indicated six DNA regions present only in We targeted one of these regions and developed a TaqMan quantitative PCR (qPCR) assay for with a detection limit of 100 CFU/ml in whole blood spiked with bacteria. screening against DNA extracted from 40 other mycobacterial species and 22 bacterial species from 21 diverse genera confirmed the -predicted specificity for Screening 33 water samples from heater-cooler units with this assay highlighted the increased sensitivity of PCR compared to culture, with 15 of 23 culture-negative samples positive by qPCR. We have thus developed a robust molecular assay that can be readily and rapidly deployed to screen clinical and environmental specimens for .
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http://dx.doi.org/10.1128/JCM.00197-17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5442541PMC
June 2017

A phylogenomic framework for assessing the global emergence and evolution of clonal complex 398 methicillin-resistant .

Microb Genom 2017 01 31;3(1):e000105. Epub 2017 Jan 31.

1​Doherty Applied Microbial Genomics, Department of Microbiology & Immunology, The University of Melbourne at The Doherty Institute for Infection and Immunity, Melbourne, Australia.

Distinct clones of methicillin-resistant (MRSA) have emerged as important causes of infection in individuals who have exposure to livestock (livestock-associated MRSA; LA-MRSA). Clonal complex 398 (CC398) is the most prevalent LA-MRSA clone, and has been reported from several geographical settings, including Europe, the Americas and Asia. To understand the factors contributing to the global dissemination of this clone, we analysed CC398 MRSA isolates from New Zealand (NZ), a geographically isolated country with an economy strongly dependent on livestock farming. We supplemented the NZ CC398 MRSA collection with global datasets of CC398 MRSA and CC398 methicillin-susceptible Here, we demonstrate multiple sporadic incursions of CC398 MRSA into NZ, as well as recent importation and spread of a swine-associated clade related to the European LA-MRSA lineage. Within a larger global phylogenomic framework, Bayesian modelling suggested that this NZ clade emerged in the late 2000s, with a probable origin in swine from Western Europe. Elucidating the factors responsible for the incursion and spread of LA-MRSA in geographically distant regions, such as NZ, provides important insights into global pathways of transmission, and will inform strategies to control importation and spread.
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http://dx.doi.org/10.1099/mgen.0.000105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5361625PMC
January 2017
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