Failure of antibiotic treatment in microbial populations

TL;DR

This paper analyzes why antibiotic treatments fail in bacterial populations, highlighting the role of persister cells, and provides mathematical conditions for treatment success or failure, suggesting that periodic dosing can sometimes outperform continuous administration.

Contribution

It offers a robust mathematical condition for treatment failure in a general chemostat model and explores how dosing schedules influence bacterial eradication.

Findings

Periodic dosing can fail to eradicate bacteria due to persister cells.

Optimal antibiotic administration may be non-monotonic, favoring periodic over continuous dosing.

The model predicts treatment outcomes regardless of initial bacterial population composition.

Abstract

The tolerance of bacterial populations to biocidal or antibiotic treatment has been well documented in both biofilm and planktonic settings. However, there is still very little known about the mechanisms that produce this tolerance. Evidence that small, non-mutant subpopulations of bacteria are not affected by antibiotic challenge has been accumulating and provides an attractive explanation for the failure of typical dosing protocols. Although a dosing challenge can kill all the susceptible bacteria, the remaining persister cells can serve as a source of population regrowth. We give a robust condition for the failure of a periodic dosing protocol for a general chemostat model, which supports the mathematical conclusions and simulations of an earlier, more specialized batch model. Our condition implies that the treatment protocol fails globally, in the sense that a mixed bacterial population will ultimately persist above a level that is independent of the initial composition of the population. We also give a sufficient condition for treatment success, at least for initial population compositions near the steady state of interest, corresponding to bacterial washout. Finally, we investigate how the speed at which the bacteria are wiped out depends on the duration of administration of the antibiotic. We find that this dependence is not necessarily monotone, implying that optimal dosing does not necessarily correspond to continuous administration of the antibiotic. Thus, genuine periodic protocols can be more advantageous in treating a wide variety of bacterial infections.