NDM-producing Klebsiella pneumoniae strains represent major clinical and infection control challenges, particularly in resource-\nlimited settings with high rates of antimicrobial resistance. Determining whether transmission occurs at a gene, plasmid,\nor bacterial strain level and within hospital and/or the community has implications for monitoring and controlling spread.\nWhole-genome sequencing (WGS) is the highest-resolution typing method available for transmission epidemiology. We sequenced\ncarbapenem-resistant K. pneumoniae isolates from 26 individuals involved in several infection case clusters in a Nepali\nneonatal unit and 68 other clinical Gram-negative isolates from a similar time frame, using Illumina and PacBio technologies.\nWithin-outbreak chromosomal and closed-plasmid structures were generated and used as data set-specific references. Three\ntemporally separated case clusters were caused by a single NDM K. pneumoniae strain with a conserved set of four plasmids, one\nbeing a 304,526-bp plasmid carrying blaNDM-1. The plasmids contained a large number of antimicrobial/heavy metal resistance\nand plasmid maintenance genes, which may have explained their persistence. No obvious environmental/human reservoir was\nfound. There was no evidence of transmission of outbreak plasmids to other Gram-negative clinical isolates, although blaNDM\nvariants were present in other isolates in different genetic contexts. WGS can effectively define complex antimicrobial resistance\nepidemiology. Wider sampling frames are required to contextualize outbreaks. Infection control may be effective in terminating\noutbreaks caused by particular strains, even in areas with widespread resistance, although this study could not demonstrate evidence\nsupporting specific interventions. Larger, detailed studies are needed to characterize resistance genes, vectors, and host\nstrains involved in disease, to enable effective intervention.
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