Abstract
Minimal inhibitory concentration-based pharmacokinetic/pharmacodynamic (PK/PD) indices are commonly applied to antibiotic dosing optimisation, but their informative value is limited, as they do not account for bacterial growth dynamics over time. We aimed to comprehensively characterise the exposure-effect relationship of levofloxacin against Escherichia coli and quantify strain-specific characteristics applying novel PK/PD parameters. In vitro infection model experiments were leveraged to explore the exposure-effect relationship of three clinical Escherichia coli isolates, harbouring different genomic fluoroquinolone resistance mechanisms, under constant levofloxacin concentrations or human concentration-time profiles (≤76 h). As an exposure metric, the 'cumulative area under the levofloxacin-concentration time curve' was determined. The antibiotic effect was assessed as the 'cumulative area between the growth control and the bacterial-killing and -regrowth curve'. PK/PD modelling was applied to characterise the exposure-effect relationship and derive novel PK/PD parameters. A sigmoidal E(max) model with an inhibition term best characterised the exposure-effect relationship and allowed for discrimination between two isolates sharing the same MIC value. Strain- and exposure-pattern-dependent differences were captured by the PK/PD parameters and elucidated the contribution of phenotypic adaptation to bacterial regrowth. The novel exposure and effect metrics and derived PK/PD parameters allowed for comprehensive characterisation of the isolates and could be applied to overcome the limitations of the MIC in clinical antibiotic dosing decisions, drug research and preclinical development.