Biofilm accumulation model that predicts antibiotic resistance of Pseudomonas aeruginosa biofilms

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Abstract
A computer model of biofilm dynamics was adapted to incorporate the activity of an antimicrobial agent on bacterial biofilm. The model was used to evaluate the plausibility of two mechanisms of biofilm antibiotic resistance by qualitative comparison with data from a well-characterized experimental system (H. Anwar, J. L. Strap, and J. W. Costerton, Antimicrob. Agents Chemother. 36:1208-1214, 1992). The two mechanisms involved either depletion of the antibiotic by reaction with biomass or physiological resistance due to reduced bacterial growth rates in the biofilm. Both mechanisms predicted the experimentally observed resistance of 7-day-old Pseudomonas aeruginosa biofilms compared with that of 2-day-old ones. A version of the model that incorporated growth rate-dependent killing predicted reduced susceptibility of thicker biofilms because oxygen was exhausted within these biofilms, leading to very slow growth in part of the biofilm. A version of the model that incorporated a destructive reaction of the antibiotic with biomass likewise accounted for the relative resistance of thicker biofilms. Resistance in this latter case was due to depletion of the antibiotic in the bulk fluid rather than development of a gradient in the antibiotic concentration within the biofilm. The modeling results predicted differences between the two cases, such as in the survival profiles within the biofilm, that could permit these resistance mechanisms to be experimentally distinguished.