Antimicrobial resistant Escherichia coli. Clinical, epidemiological and molecular characteristics in the Australian region

Background Escherichia coli is the most common gram-negative bacteria to cause human infection. The pathological manifestations range from minor disease to severe life threatening sepsis. Urinary tract infection, most often caused by E. coli, is also the most common bacterial infection in humans. Since the inception of antimicrobial therapy in the early 20th century, E. coli has systematically developed resistance to almost all known antimicrobials, posing a challenge for the treatment of such infections. From a global perspective, the first decade of the 21st century heralded a change in the epidemiology and tempo of resistance amongst E. coli. Previously, resistance to third generation cephalosporins (3GC) was primarily associated with current or previous healthcare exposure. In the past decade however, expandedspectrum cephalosporin resistant E. coli (ESC-R-EC), usually mediated by Extended Spectrum betalactamase (ESBL) genes has spread widely within the communities of many regions, independent of healthcare associated acquisition. The latter half of this decade has led to the delineation of two further challenges amongst resistant E. coli. The first is the identification of Sequence Type 131 E. coli (ST131), a global ‘pandemic’ clone fine-tuned for resistance and virulence. This clone is now implicated in a significant proportion of community ESBL E. coli infections globally. The second challenge is the emergence of E. coli harbouring carbapenemase genes, conferring resistance to carbapenem antimicrobials used to treat severe ESBL producing E. coli infection. Methods Through several studies we have aimed to better define global and local aspects of antimicrobial resistant E. coli, in particular ESC-R-EC. The studies have included clinical and laboratory based research. Clinical research included a multi-centre case-control study of community onset ESC-R-EC infection in Australia and New Zealand, and a national survey of health services’ infection control practices pertaining to multi-resistant gram-negative bacilli and patients at risk of harbouring these. Laboratory research included molecular epidemiological investigation of E. coli from two sources. The first was isolates from the 182 participants in the case-control study, comprising a broad sample of community onset 3GC resistant and susceptible E. coli from Australia and New Zealand. The second was a collection of isolates from a previously conducted study on carriage of resistant E. coli in overseas travellers returning to Australia. Results 182 patients (91 cases and 91 controls) were recruited across six tertiary hospitals in Australia and New Zealand for the case-control study. Multivariate logistic regression identified risk factors for 3GCR-EC III including birth on the Indian subcontinent (OR=11.13, 2.17-56.98, p=0.003), urinary tract infection in the past year (per infection OR=1.430, 1.13-1.82, p=0.003), travel to South East Asia, China, Indian subcontinent, Africa and the Middle East (OR=3.089, 1.29-7.38, p=0.011), prior exposure to trimethoprim+/- sulfamethoxazole &/or extended spectrum cephalosporins (OR=3.665, 1.30-10.35, p=0.014) and healthcare exposure in the previous six months (OR=3.16, 1.54-6.46, p=0.02). Molecular epidemiological analysis of isolates demonstrated a predominance of CTX-M type ESBL’s, as now reported in most other regions of the world. From a global perspective, a unique distribution of ST131 E. coli was demonstrated, with a very low prevalence of ST131 amongst 3GC susceptible isolates compared with resistant isolates (7% vs. 45%). Susceptible isolates showed diversity with six MLST defined clusters of isolates. Amongst 3GCR isolates, ST131 dominated, comprising 40/89 isolates, with 88% (35/40) of ST131 being of the recently defined fimH 30 sub-clone variant. Whilst patients with ST131 were significantly more likely to have an upper rather than lower urinary tract infection (relative risk 1.8, p=0.040), they were otherwise relatively epidemiologically homogenous with other 3GCR-EC. Analysis of isolates from returned travellers gave insight into the dynamics of carriage of antimicrobial resistant E. coli in the bowel flora and supported a number of findings from the case control study. The risk of prolonged carriage after travel was lower for 3GC-resistant than ciprofloxacin or gentamicin resistant isolates and the duration of carriage was also longer for the latter resistance phenotypes (75th quartile 8 vs. 62 and 63 days respectively). In multivariate analysis, risks of prolonged carriage included antimicrobial use whilst travelling (RR 3.3, 1.3–8.4) and phylogenetic group B2 (RR 9.3, 3.4–25.6) and D (RR 3.8, 1.6–8.8). Clonality amongst longitudinal isolates from the same participant was demonstrated in 92% of participants and most marked amongst 3GC resistant isolates. ST131 was surprisingly infrequent amongst participants (3% of participants). Conclusion Within this thesis, study of a variety of aspects of antimicrobial resistant E. coli in Australia and New Zealand has revealed unique insights into this pathogen locally and globally. These insights include the delineation of risks within the community, temporality of risk and a unique molecular epidemiology. Furthermore studies completed within this thesis highlight several key future directions of research including clinical studies to investigate risk-factor modification and optimal therapy, economic impact analyses of resistant E. coli infection, and further in-depth genetic studies.