Theoretical investigation of stochastic clearance of bacteria: First-passage analysis

Understanding mechanisms of bacterial eradication is critically important for overcoming failures of antibiotic treatments. Current studies suggest that the clearance of large bacterial populations proceeds deterministically, while for smaller populations the stochastic effects become more relevant. Here we develop a theoretical approach to investigate the bacterial population dynamics under the effect of antibiotic drugs using a method of first-passage processes. It allows us to explicitly evaluate the most important characteristics of the bacterial clearance dynamics such as extinction probabilities and extinction times. The new meaning of minimal inhibitory concentrations for stochastic clearance of bacterial populations is also discussed. In addition, we investigate the effect of fluctuations in the population growth rates on dynamics of bacterial eradication. It is found that extinction probabilities and extinction times generally do not correlate with each other when random fluctuations in the growth rates are taking place. Unexpectedly, for a significant range of parameters the extinction times increase due to these fluctuations, indicating a slowing in the bacterial clearance dynamics. It is argued that this might be one of the initial steps in the pathway for the development of antibiotic resistance. Furthermore, it is suggested that extinction times is a convenient measure of bacterial tolerance.