Does plasmid-based beta-lactam resistance increase E. coli infections: Modelling addition and replacement mechanisms

Infections caused by antibiotic-resistant bacteria have become more prevalent during past decades. Yet, it is unknown whether such infections occur in addition to infections with antibiotic-susceptible bacteria, thereby increasing the incidence of infections, or whether they replace such infections, leaving the total incidence unaffected. Observational longitudinal studies cannot separate both mechanisms. Using plasmid-based beta-lactam resistant E. coli as example we applied mathematical modelling to investigate whether seven biological mechanisms would lead to replacement or addition of infections. We use a mathematical neutral null model of individuals colonized with susceptible and/or resistant E. coli, with two mechanisms implying a fitness cost, i.e., increased clearance and decreased growth of resistant strains, and five mechanisms benefitting resistance, i.e., 1) increased virulence, 2) increased transmission, 3) decreased clearance of resistant strains, 4) increased rate of horizontal plasmid transfer, and 5) increased clearance of susceptible E. coli due to antibiotics. Each mechanism is modelled separately to estimate addition to or replacement of antibiotic-susceptible infections. Fitness costs cause resistant strains to die out if other strain characteristics are maintained equal. Under the assumptions tested, increased virulence is the only mechanism that increases the total number of infections. Other benefits of resistance lead to replacement of susceptible infections without changing the total number of infections. As there is no biological evidence that plasmid-based beta-lactam resistance increases virulence, these findings suggest that the burden of disease is determined by attributable effects of resistance rather than by an increase in the number of infections.Author summary: Infections with antibiotic-resistant bacteria (ARB) are considered a major global problem. To estimate the burden of antibiotic resistance, one should know whether, at a population level, infections with ARB replace infections with non-ARB (scenario labelled replacement) or whether infections with ARB occur on top of infections with non-ARB (scenario labelled addition). With replacement, only the additional burden of infections with ARB compared to infections with a non-ARB should be attributed to antibiotic resistance. With addition, the total burden associated with infections with ARB should be ascribed to antibiotic resistance. Using E. coli as example, we developed a mathematical model to investigate whether seven biological characteristics of ARB, each linked to either fitness costs or benefits, cause replacement or addition. A fitness cost causes resistant bacteria to die out if other characteristics are the same as for susceptible bacteria. Only increased virulence of ARB increases the total number of infections, while other benefits of resistance lead to replacement. As there is no biological evidence that the type of resistance in E. coli we studied increases virulence, these findings suggest that the burden of ARB is determined by attributable effects of resistance rather than by an increase in infections.