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Carbapenemase-producingKlebsiella pneumoniaeemerged over the past decades as an important pathogen causing morbidity and mortality in hospitalized patients. For infection prevention and control, it is important to track the spread of bacterial strains in humans including the plasmids they contain. However, little is known concerning the plasmid repertoire amongK. pneumoniaestrains. Therefore, the major aim was to recapitulate the size, contents and diversity of the plasmids of genetically relatedK. pneumoniaestrains harboring the beta-lactamase geneblaKPC-2orblaKPC-3to determine their dissemination in the Netherlands and the former Dutch Caribbean islands from 2014-2019. Next-generation sequencing was combined with long-read third-generation sequencing to reconstruct 18 plasmids ofK. pneumoniae. wgMLST revealed five genetic clusters (termed KpnClusters) comprised ofK. pneumoniae blaKPC-2isolates and four clusters consisted ofblaKPC-3isolates. Each cluster was characterized by a distinct resistome and plasmidome. KpnCluster-019blaKPC-2isolates were found both in the Netherlands and the Caribbean islands.K. pneumoniae blaKPC-3isolates were found in the collection of the Netherlands. The 18 plasmids were mostly unrelated and varied betweenK. pneumoniae blaKPC-2andblaKPC-3clusters. However, the large and medium sized plasmids contained a variety of antibiotic resistance genes, transposons, insertion sequence elements, conjugal transfer systems, cation transport systems, toxin/antitoxin systems, and prophage-related sequence elements. The small plasmids carried genes implicated in virulence. Thus, implementing long-read plasmid sequencing analysis forK. pneumoniaesurveillance provided important insights in the success and understanding of transmission of a KpnCluster-019blaKPC-2strain between the Netherlands and the Caribbean.ImportanceCarbapenemase-producingKlebsiella pneumoniaehas spread globally and is of great concern for debilitated patients.K.pneumoniaeis notorious for spreading antimicrobial resistance genes by plasmids amongEnterobacterales. Combining short and long read sequencing enables reconstruction of plasmids containing antibiotic resistance genes, conjugation machinery, transposons, toxins and/or virulence determinants and thereby enhancing international pathogen surveillance.

Background Antimicrobial stewardship is advocated to improve the quality of antimicrobial use. We did a systematic review and meta-analysis to assess whether antimicrobial stewardship objectives had any effects in hospitals and long-term care facilities on four predefined patients' outcomes: clinical outcomes, adverse events, costs, and bacterial resistance rates. Methods We identified 14 stewardship objectives and did a separate systematic search for articles relating to each one in Embase, Ovid MEDLINE, and PubMed. Studies were included if they reported data on any of the four predefined outcomes in patients in whom the specific antimicrobial stewardship objective was assessed and compared the findings in patients in whom the objective was or was not met. We used a random-effects model to calculate relative risk reductions with relative risks and 95% CIs. Findings We identified 145 unique studies with data on nine stewardship objectives. Overall, the quality of evidence was generally low and heterogeneity between studies was mostly moderate to high. For the objectives empirical therapy according to guidelines, de-escalation of therapy, switch from intravenous to oral treatment, therapeutic drug monitoring, use of a list of restricted antibiotics, and bedside consultation the overall evidence showed significant benefits for one or more of the four outcomes. Guideline-adherent empirical therapy was associated with a relative risk reduction for mortality of 35% (relative risk 0.65, 95% CI 0.54-0.80, p