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Title: Antibiotic resistance in Gram-negative bacteria in Brunei Darussalam : molecular characterisation, epidemiology, surveillance and virulence
Author: Abdul Momin, Muhd Haziq Fikry
ISNI:       0000 0004 8503 9691
Awarding Body: Queen Mary University of London
Current Institution: Queen Mary, University of London
Date of Award: 2019
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Antimicrobial resistance (AMR) presents a global threat to human and animal health. Southeast Asia (SEA) is seen as a potential hotspot for the emergence and dissemination of new resistance mechanisms. The World Health Organization highlights research on multi-drug resistant Gram-negative bacteria (Enterobacteriaceae, Acinetobacter and Pseudomonas spp) as a critical priority. This study reports findings from Brunei Darussalam. A molecular epidemiological surveillance study conducted using contemporary MDR Escherichia coli, Klebsiella pneumoniae, A. baumannii and P. aeruginosa of human and avian (farmed poultry) origin. Resistance to carbapenems and polymyxins was investigated using phenotypic (susceptibility, serotyping) and genotypic (PCR, sequencing, typing) methods. A selective bacterial culture media was developed and evaluated as a screening media for polymyxin-resistant (PR) strains. Immunochromatographic assays were used in the rapid identification of novel resistance determinants (OXA-48-like, MCR-1). Pathogenicity, fitness and virulence was correlated with host strain background and the carriage of AMR plasmids by resistant isolates. Carbapenem-resistant (CR) A. baumannii were prevalent amongst hospital isolates and produced OXA-23 carbapenemases, similar to those reported worldwide. CR K. pneumoniae (CRKP) with plasmid encoded OXA-232 carbapenemase were found as part of a hospital outbreak. All identified as members of sequence type 231, a hi-risk epidemic clone in SEA. In separate point prevalence studies, polymyxin resistant E. coli were found in 58% of poultry and 41.7% of human faecal samples. All produced phosphoethanolamine transferases encoded by mcr genes supported by diverse plasmid backbones (IncHI2, IncI2, IncX4) and host strain sequence types (n= 40). Additionally, a novel variant, mcr- 1.8, localised on a 63,056 bp IncI2 conjugative plasmid was identified and characterized in E. coli O88:H31 ST101. PR strains were co-resistant to quinolones, aminoglycosides and phenicols. CTX-M β-lactamases (CTX-M-3 and CTX-M-65) were found in 2 strains but none co-produced a carbapenemase. Comparison of human and avian MCR producing E. coli revealed only 6 sequence types were common to both humans and poultry. Polymyxin resistant strains harboured multiple virulence factors (VF) but no Avian Pathogenic (APEC) or Shiga Toxin (STEC) producing strains were found. Virulence of human and poultry isolates assessed in a Galleria mellonella infection model showed differences in survival rates that did not correlate with virulence score. When virulence of polymyxin resistant transconjugants (TC) was assessed only one which encoded MCR-1.8 exhibited heightened virulence. Growth kinetics showed no obvious differences despite plasmid acquisition. This study demonstrates the high rate of resistance to carbapenems and polymyxins in critical Gram-negative bacteria in Brunei Darussalam. Plasmidmediated polymyxin resistance in E. coli was found to be endemic in poultry and highly prevalent in the human samples studied. Unlike carbapenem resistance, polymyxin resistance was not associated with any predominant clone and did not readily correlate with virulence properties of the strain. However, given the high background rates, enhanced surveillance for MCR-1 within more virulent Enterobacterial backgrounds is warranted, particularly in Southeast Asia countries.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Medicine and Dentistry ; Antimicrobial resistance ; Southeast Asia ; Gram-negative pathogens ; Mechanisms of resistance