A three-dimensional cellular automata model of biofilm dynamics was adapted to simulate the protection from killing by antimicrobial agents afforded to microorganisms in the biofilm state. The model incorporated diffusion and simultaneous utilization of a single substrate, growth and displacement of cells, detachment, and killing by an antimicrobial agent. The rate of killing was assumed to be directly proportional to the local concentration of substrate available to the microorganisms. Some of the features predicted by this model included development of dynamic, heterogeneous biofilm structures, gradients in substrate concentration leading to regions of substrate depletion in the interior of large cell clusters, variable killing by an antimicrobial agent from one simulation to the next, greater killing of cells at the periphery of cell clusters compared to those cells which were more deeply embedded, and reduced overall antimicrobial susceptibility of cells in the biofilm. These simulations show that substrate limitation can contribute to the protection from antimicrobial agents in biofilms but cannot explain the long-term persistence of biofilm viability that is often observed in practice.

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