Novel Pharmacokinetic/Pharmacodynamic Parameters Quantify the Exposure-Effect Relationship of Levofloxacin against Fluoroquinolone-Resistant Escherichia coli.

Johanna Seeger,Sebastian Guenther,Charlotte Kloft,Robin Michelet,Katharina Schaufler,Stefan E Heiden

doi:10.3390/antibiotics10060615

Johanna Seeger, Sebastian Guenther + Show 4 more

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https://doi.org/10.3390/antibiotics10060615

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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 Emax 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.

Highlights

IntroductionDosing optimisation is an important strategy to tackle the global threat of antimicrobial resistance and is commonly based on pharmacokinetic/pharmacodynamic (PK/PD)
minimal inhibitory concentration (MIC) values classified the three isolates as LVX-resistant according to European Committee on Antimicrobial Susceptibility Testing (EUCAST) [33]
Based on the approach introduced by Firsov et al, we went beyond the MIC and introduced novel parameters, capturing the different processes constituting the antibiotic effect, i.e., killing and regrowth under antibiotic exposure over time—initially, the sigmoidal Emax model term dominated the exposure–effect relationship, while the impact of the inhibition term increased at higher cumulative exposure values at later timepoints

Summary

Introduction

Dosing optimisation is an important strategy to tackle the global threat of antimicrobial resistance and is commonly based on pharmacokinetic/pharmacodynamic (PK/PD). Indices, which relate an exposure metric of an antibiotic, e.g., Cmax or AUC, to an effect metric, the minimal inhibitory concentration (MIC) of the pathogen [1,2,3]. Limitations of the MIC value in predicting in vivo susceptibility of pathogens are well known: 2-fold dilution series of antibiotic concentrations are conventionally used, with visual evaluation after. MIC values of a bacterial wild-type population usually cover 3–5 two-fold dilutions [8] and clinical decision-making, guided by MIC-based PK/PD indices, entails a risk of inappropriate categorisation of the bacterial strain. Choice of an inefficacious antibiotic and dosing regimen can result in treatment failure

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