Emerging antimicrobial resistance offers opportunities to better understand and limit antibiotic resistance

Johannetsy Joayleen Avillan

doi:10.7273/000005114

The distribution of antimicrobial resistance across different host populations and diverse environments presents a significant threat for public health worldwide. Novel antibiotic-resistance traits, such as β-lactam-resistance genes (β-lactamases) can be introduced into naïve bacterial populations, but successful establishment within the population will depend on the fitness cost of these traits in the absence of antibiotic selection pressure, and the relative fitness advantages that are conveyed by these traits in the presence of antibiotics. In contrast, when bacteria with novel antimicrobial resistance genes enter a population where a similar spectrum of resistance already exists, it is unclear what conditions are needed for the novel gene to become established in the population. The interaction between these populations (having resident or novel traits), modulated by fitness costs and benefits, will determine if the novel trait will become established in the naïve population. This dissertation aims at identifying the parameters that influence the fitness of βlactamase-producing strains of Enterobacteriaceae (Chapters 2) by comparing phenotypically, kinetically, and transcriptionally the fitness costs and benefits of three β-lactamases (CTX-M-15, CMY-2 and KPC-3). Additionally, we examined how hydrolysis varies for ampicillin, ceftiofur and the different antibacterial ceftiofur metabolites (desfuroylceftiofur (DFC), DFC-cysteine, and DFC-dimer) that are generated after ceftiofur is administered (Chapters 2). Characteristics driving successful colonization and persistence in the new populations have been an important knowledge gap, especially when a novel resistance trait enters a population in which another resistance trait is already present and consequently competes with the colonizing trait. A scenario like this has been documented in the Washington State dairy herds (Chapter 1) where almost all ceftiofur-resistant E. coli isolates before 2009 were blaCMY-2-positive. In 2011, blaCTX-M (mostly blaCTX-M-15) was first documented with low prevalence (14.8%). In late 2015, the prevalence of blaCMY-2-positive E. coli reduced to 38.1%, while the prevalence of blaCTX-M increased to 26.2% (Chapter 1). In the dairies, ampicillin and ceftiofur (a 3 rd -generation cephalosporin) are the primary β-lactams used to treat non-mastitis infections. Both CMY-2 and CTX-M-15 convey resistance to both antibiotics. In the absence of competing genes, E. coli harboring either gene can experience a selective advantage if exposed to these antibiotics (Chapter 2). Successful emergence of CTX-M-15-producing strains where CMY-2-producing strains are already established, however, requires high concentrations of antibiotics that can only be found in the urine of treated animals (e.g., known to achieve >2 mg/ml for ampicillin) (Chapter 2). These findings are consistent with selection ex vivo driving the expansion of CTX-M-15-producing strains at the expense of CMY-2-producing strains, and these high environmental concentrations of antibiotics are likely to be important for selecting other antibiotic-resistant traits.

Emerging antimicrobial resistance offers opportunities to better understand and limit antibiotic resistance

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