Synopsis
Background The quantitative determination of the effects of antimicrobials is essential for our understanding of pharmacodynamics and for their rational clinical application. However, common pharmacodynamic measures of antimicrobial efficacy, such as the MIC and the pharmacodynamic function, fail to capture the observed dependence of efficacy on the bacterial population size — a phenomenon called inoculum effect.
Objectives We aimed to assess the relationship between bacterial inoculum size and pharmacodynamic parameters, and to determine the consequences of the inoculum effect on bacterial population dynamics under treatment with antimicrobials.
Methods We used the mathematical multi-hit model to quantify the effect of the inoculum on the pharmacodynamic parameters. The model describes antimicrobial action mechanistically, which allowed us to test various hypotheses concerning the mechanistic basis of the inoculum effect.
Results Our model showed that the inoculum effect can arise from the binding dynamics of antimicrobial molecules to bacterial targets alone and does not require enzymatic degradation of antimicrobials. With enzymatic degradation, however, the inoculum effect is more pronounced. We propose to include the inoculum effect when measuring antimicrobial efficacy, i. e. to extend the pharmacodynamic function with the inoculum effect. This extended pharmacodynamic function mimiced simple long-term population dynamics well. More complex scenarios were only captured with the mechanism-based multi-hit model. In simulations with competing antimicrobial-sensitive and -resistant bacteria, neglecting the inoculum effect lead to an overestimation of the competitive ability of the resistant strain.
Conclusions Our work emphasizes that the pharmacodynamic function — and in general any efficacy measure, e.g. the MIC — should include information about the inoculum size on which it is based, and ideally account for the inoculum effect.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
Text and figures were updated and improved.