Date of Award

6-2015

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Philosophy

First Advisor

Dr. Agnes onnevend

Second Advisor

Dr. Mariam AI Shamsi

Third Advisor

Professor Salim Bastaki

Abstract

The efficient control of the spread of carbapenemase producer Enterobacteriaceae, a major public health threat world-wide, requires knowledge on the molecular epidemiology and genetic background of the emerging carbapenemase genes.

Our aim was to investigate the genetic support of New-Delhi metallo-beta-lactamase and OXA-48-type carbapenemase genes in carbapenem resistant Enterobacteriaceae isolated in the United Arab Emirates. Since these isolates are extremely drug resistant, leaving few treatment options, the efficacy of alternative antimicrobials was also assessed.

Seven NDM-producer Enterobacteriaceae, collected during 2009-2011, and subsequently five NDM and OXA-48-type carbapenemase co-producer Klebsiella pneumoniae isolated during 2011-2013 in three hospitals of the Emirates, were characterized. Strains' clonality and the transmissibility of carbapenemase genes were assessed. The genetic support of carbapenemases was studied by characterization of plasmids and by sequencing the surrounding regions. Furthermore, the effect of the himenochirin-1 B analogue antimicrobial peptide was tested on selected strains. Moreover, the fosfomycin susceptibility of 45 carbapenem non-susceptible Escherichia coli isolates was tested.

Three K. pneul11oniae, two Escherichia coli, one Enterobacter cloacae and one Citrobacter freundii were found to produce NDM-1 carbapenemase. Epidemiological link was established in case of two K. pneumoniae strains. All isolates harbored the blaNDM-1 gene on conjugative plasmids. Furthermore, IncX3 plasmids with almost identical restriction patterns were present in E. cloacae, E. coli and C. fieundii. The self-conjugative NDM plasmid showed high similarity to these in one of the clonally unrelated K. pneumoniae co-producing OXA-48 also. Three of the five double carbapenemase producer ST14 K. pneumoniae possessing blaNDM-1 and blaOXA-232, the former one on conjugative, the latter one non-conjugative plasmid, were clonally related. The fifth, unrelated K. pneumoniae co -produced NDM-l and OXA-162. All E. coli isolates remained susceptible to fosfomycin. Low concentration of himenochirin-1B analogue inhibited the growth of all selected NDM-producers.

We have proved that IncX3 plasmids play an important role in the inter-species spread of the blaNDM gene. We demonstrated that the emergence of NDM- and OXA- 48-type carbapenemase co-producer K. pneumoniae is partially a clonal phenomenon. We found that fosfomycin is a valuable therapeutic option against E. coli. Additionally, we demonstrated the efficacy of [E6k, D9k]hymenochirin-lB against carbapenem resistant Enterobacteriaceae.

Share

COinS