Stochastic effects on the establishment of mutants resistant to β-lactam antibiotics

For antibiotic resistance to arise, new resistant mutants must establish in a bacterial population before they can spread via natural selection. Understanding the stochastic factors influencing mutant establishment is crucial for a quantitative understanding of antibiotic resistance emergence. Here, we quantify the single-cell establishment probability of four Escherichia coli strains expressing β-lactamase alleles with different activity against the antibiotic cefotaxime, as a function of concentration. Using a simple branching model, we show that concentrations well below the minimal inhibitory concentration (MIC) can substantially hamper establishment, particularly for highly resistant mutants, suggesting cooperative effects due to antibiotic breakdown at high cell densities. We further show that variation among cell lineages may explain the more gradual influence of increased antibiotic concentrations on agar. Finally, we use the single-cell establishment probability to predict a strain’s MIC in the absence of social interactions, as a general reference to detect cooperative resistance effects.