Βeta-lactamases Dissemination amongst Multidrug-resistant Pathogenic Enterobacteriaceae Isolated in Pakistan and the United States

Abstract

Increasing resistance to modern antimicrobials in Enterobacteriaceae is a global health concern. Carbapenem resistant Enterobacteriaceae (CRE), encoding carbapenemases such as New Delhi Metallo-β -lactamase-1 (NDM-1) or Klebsiella pneumoniae Carbapenemase (KPC), are emerging threats. CREs harboring NDM are highly prevalent in the Indian subcontinent, while KPC isolates are globally distributed. Accurate genomic-based diagnostics of these and other multidrug resistant (MDR) pathogens could enable more rapid and efficacious treatment of bacterial infections. In this study, whole genome sequencing (WGS) was performed on 78 isolates of Enterobacteriaceae recovered from clinical samples in Pakistan and U.S.A. For each isolate high-resolution phylogenetic determination, antibiotic resistance and virulence gene detection, antibiotic susceptibility profile prediction, and antibiotic susceptibility phenotype validation was performed. Highly related bacteria were identified in Pakistani and U.S. samples harboring identical β-lactamases, and it was found that total antibiotic resistance gene carriage was not significantly different between locations. Though KPC was only identified in U.S. isolates and NDM-1 was identified in Pakistani isolates only, overall β-lactamase genotypes did not correlate with phylogeny or point of origin. When all sequenced plasmids carrying KPC or NDM-1 available on NCBI were compared, including plasmids from U.S. and Pakistani isolates, plasmids carrying either carbapenamase were similarly diverse in sequences. The presence of NDM-1 in diverse plasmid backbones and widely distributed pathogenic bacterial strains suggests that it is poised for global dissemination. WGS has a high potential for accurate detection of susceptibility profile of MDR pathogens such as CREs carrying carbapenemases.