Tracking inter-institutional spread of NDM and identification of a novel NDM-positive plasmid, pSg1-NDM, using next-generation sequencing approaches

Khong, Wei Xin; Marimuthu, Kalisvar; Teo, Jeanette; Ding, Yichen; Xia, Eryu; Lee, Jia Jun; Ong, Rick Twee‐Hee; Venkatachalam, Indumathi; Cherng, Benjamin Pei Zhi; Pada, Surinder; Choong, Weng Lam; Smitasin, Nares; Ooi, Say Tat; Deepak, Rama Narayana; Kurup, Asok; Fong, Raymond Kok Choon; La, My-Van; Tan, Thean Yen; Koh, Tse Hsien; Lin, Raymond Tzer Pin; Tan, Eng Lee; Krishnan, Prabha; Singh, Siddharth; Pitout, Johann; Teo, Yik-Ying; Yang, Liang; Ng, Oon Tek

doi:10.1093/jac/dkw277

Cited by 33 publications

(26 citation statements)

References 41 publications

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“…At the global scale, we identified several high-risk clones of E. coli ST410, with evidence of frequent international transmission, in agreement with a previous report (19). Previous reports of carbapenem-resistant E. coli ST410 from the Western Pacific and South East Asia regions described the presence of blaOXA-181 in China (18,37), blaNDM-1 in Singapore (38), blaNDM-5 in South Korea (39), or the combination of blaNDM-5 and blaOXA-181 in Myanmar (40) and South Korea (39). The repertoire of carbapenemases in the retrospective collection of ST410 from the Philippines seemed to be in tune with the genes/variants circulating locally, as most isolates carried the prevalent variant blaNDM-1.…”

Section: Discussionsupporting

confidence: 90%

See and Sequence: Integrating Whole-Genome Sequencing Within the National Antimicrobial Resistance Surveillance Program in the Philippines

Argimón¹,

Masim

Gayeta

et al. 2019

Preprint

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Background. Drug-resistant bacterial infections constitute a growing threat to public health globally. National networks of laboratory-based surveillance of antimicrobial resistance (AMR) monitor the emergence and spread of resistance and are central to the dissemination of these data to AMR stakeholders. Whole-genome sequencing (WGS) can support these efforts by pinpointing resistance mechanisms and uncovering transmission patterns. We implemented WGS within the established Antimicrobial Resistance Surveillance Program (ARSP) of the Philippines. We aimed to employ WGS to characterize bacterial populations and dissect resistance phenotypes of key bug-drug combinations, thus establishing a genetic background to contextualize local prospective surveillance.Methods. We sequenced the genomes from eight bacterial pathogens collected between 2013 and 2014 by the ARSP, and conducted phylogenetic analyses, in silico genotyping, genomic predictions of AMR, and characterization of key plasmids carrying carbapenemase genes. Here, we focus on carbapenemase-producing organisms.Findings. ARSP phenotypic data indicated increasing carbapenem resistance for Pseudomonas aeruginosa, Acinetobacter baumannii, Klebsiella pneumoniae and Escherichia coli, with marked expansion of specific resistance phenotypes. By linking resistance phenotypes to genomic data, we revealed the diversity of genetic lineages (strains), AMR mechanisms, and AMR vehicles underlying this expansion. We discovered a previously unidentified plasmid-driven hospital outbreak of carbapenem-resistant K. pneumoniae, uncovered the interplay of carbapenem resistance genes and plasmids in the geographic circulation of international epidemic K. pneumoniae ST147, and found that carbapenem-resistant E. coli ST410 were represented by diverse lineages of global circulation that both conserved international plasmids and acquired plasmids of local circulation.Conclusions. WGS provided an enhanced understanding of the interplay between strains, genes and vehicles driving the dissemination of carbapenem resistance in the Philippines. We generated a blueprint for the integration of WGS and genomic epidemiology into an established national system of laboratory-based surveillance of AMR through international collaboration. Continued prospective sequencing, capacity building and collaboration will strengthen genomic surveillance of AMR in the Philippines and the translation of genomic data into public-health action.

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Section: Discussionsupporting

confidence: 90%

See and Sequence: Integrating Whole-Genome Sequencing Within the National Antimicrobial Resistance Surveillance Program in the Philippines

Argimón¹,

Masim

Gayeta

et al. 2019

Preprint

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“…The first case of NDM-1 was described in 2009 when a Swedish patient of Indian origin who traveled to New Delhi contracted a urinary tract infection resulting from NDM-1 producing K. pneumoniae ( Yong et al, 2009 ). The first local cases of NDM-1 was identified in 2010 in an Indian and Bangladeshi national, and since then there has been a progressive increase of locally transmitted cases ( Chien et al, 2012 ) mediated by bla NDM bearing plasmids in K. pneumoniae and E. coli ( Khong et al, 2016 ). In our study, a range of other carbapenemases including class B metallo-beta lactamases ( bla NDM , bla IMP , bla V IM ), were detected at lower abundance than bla KPC-2 .…”

Section: Discussionmentioning

confidence: 99%

Characterization of Metagenomes in Urban Aquatic Compartments Reveals High Prevalence of Clinically Relevant Antibiotic Resistance Genes in Wastewaters

Tay

Tan

et al. 2017

Front. Microbiol.

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The dissemination of antimicrobial resistance (AMR) is an escalating problem and a threat to public health. Comparative metagenomics was used to investigate the occurrence of antibiotic resistant genes (ARGs) in wastewater and urban surface water environments in Singapore. Hospital and municipal wastewater (n = 6) were found to have higher diversity and average abundance of ARGs (303 ARG subtypes, 197,816 x/Gb) compared to treated wastewater effluent (n = 2, 58 ARG subtypes, 2,692 x/Gb) and surface water (n = 5, 35 subtypes, 7,985 x/Gb). A cluster analysis showed that the taxonomic composition of wastewaters was highly similar and had a bacterial community composition enriched in gut bacteria (Bacteroides, Faecalibacterium, Bifidobacterium, Blautia, Roseburia, Ruminococcus), the Enterobacteriaceae group (Klebsiella, Aeromonas, Enterobacter) and opportunistic pathogens (Prevotella, Comamonas, Neisseria). Wastewater, treated effluents and surface waters had a shared resistome of 21 ARGs encoding multidrug resistant efflux pumps or resistance to aminoglycoside, macrolide-lincosamide-streptogramins (MLS), quinolones, sulfonamide, and tetracycline resistance which suggests that these genes are wide spread across different environments. Wastewater had a distinctively higher average abundance of clinically relevant, class A beta-lactamase resistant genes (i.e., blaKPC, blaCTX-M, blaSHV, blaTEM). The wastewaters from clinical isolation wards, in particular, had a exceedingly high levels of blaKPC-2 genes (142,200 x/Gb), encoding for carbapenem resistance. Assembled scaffolds (16 and 30 kbp) from isolation ward wastewater samples indicated this gene was located on a Tn3-based transposon (Tn4401), a mobilization element found in Klebsiella pneumonia plasmids. In the longer scaffold, transposable elements were flanked by a toxin–antitoxin (TA) system and other metal resistant genes that likely increase the persistence, fitness and propagation of the plasmid in the bacterial host under conditions of stress. A few bacterial species (Enterobacter cloacae, Klebsiella pneumoniae, Citrobacter freundii, Pseudomonas aeruginosa) that were cultured from the isolation ward wastewaters on CHROMagar media harbored the blaKPC-2 gene. This suggests that hospital wastewaters derived from clinical specialty wards are hotspots for the spread of AMR. Assembled scaffolds of other mobile genetic elements such as IncQ and IncF plasmids bearing quinolone resistance genes (qnrS1, qnrS2) and the class A beta-lactamase gene (blaTEM-1) were recovered in wastewater samples which may aid the transfer of AMR.

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“…Eight transmission clusters were detected, of which 3 had evidence of inter-institutional transmission. Prior work in Singapore focused on bla NDM involving 29 patients and 4 institutions uncovered 5 transmission clusters of which 2 were inter-institutional [23]. A recent modeling effort from the US Centers for Disease Control and Prevention (CDC) projected that a coordinated, regional effort to prevent carbapenem-resistant enterobacteriaceae would result in between 55% and 74% cumulative reductions in acquisitions, depending on network size [24].…”

Section: Discussionmentioning

confidence: 99%

Clinical and Molecular Epidemiology of Carbapenem-Resistant Enterobacteriaceae Among Adult Inpatients in Singapore

Marimuthu

Venkatachalam

Khong

et al. 2017

Clinical Infectious Diseases

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Background. Since 2010, the incidence of carbapenem-resistant Enterobacteriaceae (CRE) has been increasing in Singapore. We analyzed the clinical and molecular epidemiology of CRE among adult inpatients in Singapore.Methods. Quarterly incidence of unique subjects (per 100 000 patient-days) with positive clinical and surveillance cultures for CRE were estimated based on mandatory data submitted to the National Public Health Laboratory by public hospitals between 2010 and 2015. CRE-positive adult inpatients were prospectively recruited from 6 public sector hospitals between December 2013 and April 2015. Subjects answered a standardized epidemiologic questionnaire and provided samples for this study. Further clinical information was extracted from subjects' electronic medical records. Whole-genome sequencing was performed on study isolates to determine transmission clusters.Results. Incidence of CRE clinical cultures among adult inpatients plateaued from 2013 (range: 7.73 to 10.32 per 100 000 patient-days) following an initial increase between 2010 and end-2012. We prospectively recruited 249 subjects. Their median age was 65 years, 108 (43%) were female, and 161 (64.7%) had carbapenemase-producing Enterobacteriaceae (CPE). On multivariate analysis, prior carbapenem exposure (OR: 3.23; 95% CI: 1.67-6.25) and hematological malignancies (OR: 2.85; 95% CI: 1.10-7.41) were associated with non-carbapenemase-producing CRE (NCPE) (n = 88) compared with CPE (n = 161) subjects. Among 430 CRE isolates from the 249 subjects, 307(71.3%) were CPE, of which 154(50.2%) were bla KPC -positive, 97(31.6%) bla NDM -positive, and 42 (13.7%) bla OXA -positive. Klebsiella pneumoniae (n = 180, 41.9%), Escherichia coli (n = 129, 30.0%) and Enterobacter cloacae (n = 62, 14.4%) were the main Enterobacteriaceae species. WGS (n = 206) revealed diverse bacterial strain type (STs). The predominant bla KPC -positive plasmid was pHS102707 (n = 62, 55.4%) and the predominant bla NDM -positive plasmid was pNDM-ECS01 (n = 46, 48.9%). Five transmission clusters involving 13 subjects were detected.Conclusions. Clinical CRE trend among adult inpatients showed stabilization following a rapid rise since introduction in 2010 potentially due to infection prevention measures and antimicrobial stewardship. More work is needed on understanding CPE transmission dynamics.

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Tracking inter-institutional spread of NDM and identification of a novel NDM-positive plasmid, pSg1-NDM, using next-generation sequencing approaches

Cited by 33 publications

References 41 publications

See and Sequence: Integrating Whole-Genome Sequencing Within the National Antimicrobial Resistance Surveillance Program in the Philippines

See and Sequence: Integrating Whole-Genome Sequencing Within the National Antimicrobial Resistance Surveillance Program in the Philippines

Characterization of Metagenomes in Urban Aquatic Compartments Reveals High Prevalence of Clinically Relevant Antibiotic Resistance Genes in Wastewaters

Clinical and Molecular Epidemiology of Carbapenem-Resistant Enterobacteriaceae Among Adult Inpatients in Singapore

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