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Klebsiella pneumoniae is a major human pathogen responsible for high morbidity and mortality rates. The emergence and spread of strains resistant to multiple antimicrobial agents and documented large nosocomial outbreaks are especially concerning. To develop new therapeutic strategies for K. pneumoniae , it is imperative to understand the population genomic structure of strains causing human infections. To address this knowledge gap, we sequenced the genomes of 1,777 extended-spectrum beta-lactamase-producing K. pneumoniae strains cultured from patients in the 2,000-bed Houston Methodist Hospital system between September 2011 and May 2015, representing a comprehensive, population-based strain sample. Strains of largely uncharacterized clonal group 307 (CG307) caused more infections than those of well-studied epidemic CG258. Strains varied markedly in gene content and had an extensive array of small and very large plasmids, often containing antimicrobial resistance genes. Some patients with multiple strains cultured over time were infected with genetically distinct clones. We identified 15 strains expressing the New Delhi metallo-beta-lactamase 1 (NDM-1) enzyme that confers broad resistance to nearly all beta-lactam antibiotics. Transcriptome sequencing analysis of 10 phylogenetically diverse strains showed that the global transcriptome of each strain was unique and highly variable. Experimental mouse infection provided new information about immunological parameters of host-pathogen interaction. We exploited the large data set to develop whole-genome sequence-based classifiers that accurately predict clinical antimicrobial resistance for 12 of the 16 antibiotics tested. We conclude that analysis of large, comprehensive, population-based strain samples can assist understanding of the molecular diversity of these organisms and contribute to enhanced translational research. IMPORTANCE Klebsiella pneumoniae causes human infections that are increasingly difficult to treat because many strains are resistant to multiple antibiotics. Clonal group 258 (CG258) organisms have caused outbreaks in health care settings worldwide. Using a comprehensive population-based sample of extended-spectrum beta-lactamase (ESBL)-producing K. pneumoniae strains, we show that a relatively uncommon clonal type, CG307, caused the plurality of ESBL-producing K. pneumoniae infections in our patients. We discovered that CG307 strains have been abundant in Houston for many years. As assessed by experimental mouse infection, CG307 strains were as virulent as pandemic CG258 strains. Our results may portend the emergence of an especially successful clonal group of antibiotic-resistant K. pneumoniae ., (Copyright © 2017 Long et al.)

Study Objective: Our understanding of the molecular dynamics driving the community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) epidemic at the whole genome level is limited. We sought to assess the use of whole genome sequencing (WGS) to evaluate the genomic diversity and genotypic prediction of antimicrobial resistance of CA-MRSA isolates from patients in South Texas., Design: Comparative whole genome sequencing., Isolates: Thirteen clinical CA-MRSA isolates recovered from patients presenting with skin and soft tissue infections to nine primary care clinics in the South Texas Ambulatory Research Network between 2010 and 2013., Measurements and Main Results: Comparative WGS was performed on the 13 MRSA sequence type 8 clinical isolates. We compared the resistome of genes encoding for antibiotic resistance with a phenotypically derived antibiogram using standard antimicrobial susceptibility testing. The strains differed by an average of 72 single nucleotide polymorphisms (SNPs) per isolate in the core genome compared with FPR3757 (USA300, reference strain). There were a total of 623 unique SNPs in the core genome (range 47-88 SNPs per isolate). We identified 19 nonsynonymous SNPs in genes encoding proven or putative S. aureus virulence determinants in the core genome. There was complete concordance between genotypic evidence for antimicrobial resistance and the phenotypically derived antibiogram., Conclusion: Overall, although these CA-MRSA isolates were similar on the level of clonal type, clinical syndrome, and geographic area, the strains were diverse at the genome level. Furthermore, our findings provide important proof-of-concept information for using WGS as a potential front-end screening tool for antimicrobial resistance predictions., (© 2015 Pharmacotherapy Publications, Inc.)