Genomic Epidemiology of NDM-producing enterobacteria from Brazil

Abstract

Healthcare associate infections (HAIs) caused by multi-resistant microorganisms pose a challenging to clinical practice, as they have a negative impact on associated morbidity, lethality, hospitalization time and costs generated to the health system. Gram-negative bacilli with resistance to multiple antimicrobials, including carbapenems and polymyxins, are currently the most worrying, since the emergence of extensively and even pan-drug-resistant strains is already a reality, especially in hospitals of greater complexity. In Brazil, hyperendemic rates of carbapenem-resistant enterobacteria are reported, mainly due to Klebsiella pneumoniae carbapenemase (KPC)-producing isolates, which are disseminated in several institutions. Conversely, the increasing polymyxin resistance rates in KPC-producing enterobacteria are also reported. One of the recently released alternative against KPC-producing enterobacteria is the new association of antimicrobials ceftazidime-avibactam (CAZ-AVI), with activity on KPC producing isolates. However, CAZ-AVI does not present activity against another subclass of carbapenemase enzymes, the metallo-beta-lactamases (MBL). Among the most frequent MBL variants in enterobacteria in Brazil, the New Delhi Metalobetalactamase (NDM) stands out. NDM was initially described in isolates from Asia but the first case in an invasive clinical isolate of K. pneumoniae was reported in Brazil in 2016, by our group. Since then, NDM-producing K. pneumoniae has been consistently reported in our country, even if still in relatively low proportions. As the Central Public Health Laboratory (LACEN) in the most populous state of the Federation, the Adolfo Lutz Institute receives isolates from several hospitals for characterization and molecular surveillance of antimicrobial resistance. The introduction of a new antimicrobial that does not cover this type of resistance must be carefully monitored, since there are already reports of substitution of KPC for MBL in medical centers that have not used CAZ-AVI in a more rational way. The horizontal transmission of KPC is known to be mediated by Tn4401-like transposon carrier plasmids, however, for NDM this characterization is not well understood. Furthermore, the mechanism of transmission by microvesicles (MVs), which could be independent of the plasmidial machinery, is a new possibility of dispersion, since NDM enzymes have the peculiar ability to anchor to the bacterial plasmatic membrane. In addition to the enzyme, bacterial DNA can also compose the content of MVs. Thus, this study aims to evaluate the behavior of isolates of NDM-producing enterobacteria after the introduction of a new antimicrobial. Through high definition genomic analysis, the core genome and accessory genomes (plasmids) will be sequenced to elucidate transmission mechanisms. We will also study the role of microvesicles as a potential mechanism for the dissemination of genes encoding NDM in these enterobacteria. (AU)