Investigation of a hospital Enterobacter cloacae NDM-1 outbreak using whole genome sequencing

Abstract

Caprbapenemase-producing Gram-negative micro-organisms are emerging as a major clinical problem. The infections caused by these highly resistant and hospital-adapted pathogens may become untreatable using existing antibiotics. Over a three year period, six patients at a large UK tertiary-referral hospital were colonised or infected with carbapenem-resistant Enterobacter cloacae carrying the blaNDM-1 metallo-β-lactamase gene. Environmental isolates were also obtained from a clinical wash-hand basin and taps. The isolates had very similar pulsed-field gel electrophoresis profiles, suggesting they were related, although only four of the cases had epidemiological links. Whole genome sequencing showed the isolates had the same genomic background (sequence type ST114). Genes encoding seven different extended-spectrum and inhibitor-resistant β-lactamase and carbapenemase enzymes (blaNDM-1; blaCTX-M-15; blaACT-16; blaVEB-1; blaTEM-1; blaOXA-1 and blaOXA-10) were present, in addition to multiple genes and mutations conferring resistance to aminoglycosides, quinolones, trimethoprim, tetracycline, sulphonamide, chloramphenicol, rifampicin and fosfomycin. Phenotypic testing indicated sensitivity only to colistin and tigecycline. Genome-wide single nucleotide polymorphism analysis showed the four linked isolates were closely related, and differed from the unlinked isolates by 16–24 SNPs. Moreover, resistance encoding plasmids had been lost in the two unlinked isolates. This suggested these isolates, although sharing a recent common ancestor, had evolved in different environments. Whole genome sequencing allowed resolution of very closely related E. cloacae strains, and confirmed the outbreak did not extend beyond the linked patients. Sequencing also confirmed the same highly resistant E. cloacae strain had persisted within a clinical unit for over two years, despite rigorous efforts to eradicate it.

IS26-Mediated Transfer of blaNDM–1 as the Main Route of Resistance Transmission During a Polyclonal, Multispecies Outbreak in a German Hospital

“…Since carbapenems belong to the most important last resort antibiotics for the treatment of infections caused by MDR Gram-negative bacteria, the emergence of bacteria producing carbapenem hydrolysing enzymes is of particular interest. KPC-2 producing strains, especially K. pneumoniae, have been frequently reported in Europe; whereas the number of reports on NDM-1 producers is much smaller (ECDC, 2019;Fairley et al, 2019;Hernandez-Garcia et al, 2019). Hospital-associated infections caused by NDM-1-producing Enterobacterales have recently been described in Spain, England, and Italy (ECDC, 2019;Fairley et al, 2019;Hernandez-Garcia et al, 2019).…”

“…KPC-2 producing strains, especially K. pneumoniae, have been frequently reported in Europe; whereas the number of reports on NDM-1 producers is much smaller (ECDC, 2019;Fairley et al, 2019;Hernandez-Garcia et al, 2019). Hospital-associated infections caused by NDM-1-producing Enterobacterales have recently been described in Spain, England, and Italy (ECDC, 2019;Fairley et al, 2019;Hernandez-Garcia et al, 2019). In Germany, screening for "carbapenem-resistant Enterobacterales and A. baumanii including NDM-1-producing bacteria" is currently only recommended for patients who were previously admitted to hospitals in "high-risk countries" such as India, Pakistan and the Balkan states (KRINKO, 2012).…”

“…Isolates belonging to the largest clonal clusters formed by E. coli ST744 (n = 9) and ST6332 (n = 7) were detected almost within the entire screening period. Clonal spread of NDM-1-positive species have been described in various parts of the world mainly caused by K. pneumoniae and E. cloacae (Jin et al, 2015;Mahida et al, 2017;Bocanegra-Ibarias et al, 2019;Fairley et al, 2019;Monteiro et al, 2019). Nosocomial outbreaks caused by K. pneumoniae ST39, ST37, and ST307 have also been reported worldwide (Belbel et al, 2014;Zhu et al, 2016;Bocanegra-Ibarias et al, 2019).…”

“…The reliable reconstruction of transmission chains is therefore essential to the analysis of multispecies outbreaks, although often difficult and laborious (Pirs et al, 2019). Outbreaks of NDM-1-producing Enterobacterales have been reported, as described for the United Kingdom (Fairley et al, 2019), Greece (Politi et al, 2019), Poland (Baraniak et al, 2016), Slovenia (Pirs et al, 2019), Belgium (Heinrichs et al, 2019), Netherlands (Bosch et al, 2017), and most recently Italy (ECDC, 2019). In Europe and more particular in Germany, the prevalence of invasive Enterobacterales with resistance to carbapenems is still low, and NDM-1-producing isolates have only been observed occasionally (Becker et al, 2018b).…”

Characterization of a New Transposon, Tn6696, on a blaNDM–1-Carrying Plasmid From Multidrug-Resistant Enterobacter cloacae ssp. dissolvens in China

“…Prevalence of NDM-1-carrying E. cloacae was observed in France (Perry et al, 2011) and Mexico (Torres-Gonzalez et al, 2015). Genome sequencing and analysis also revealed an NDM-1 E. cloacae outbreak in a hospital in the UK (Fairley et al, 2019). In the southwest region of China, 132 carbapenem-resistant E. cloacae isolates were obtained from patients between 2012 and 2016.…”