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Predicting Antimicrobial Activity at the Target Site: Pharmacokinetic/Pharmacodynamic Indices versus Time–Kill Approaches

Antibiotic dosing strategies are generally based on systemic drug concentrations. However, drug concentrations at the infection site drive antimicrobial effect, and efficacy predictions and dosing strategies should be based on these concentrations. We set out to review different translational pharma...

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Autores principales: van Os, Wisse, Zeitlinger, Markus
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8698708/
https://www.ncbi.nlm.nih.gov/pubmed/34943697
http://dx.doi.org/10.3390/antibiotics10121485
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author van Os, Wisse
Zeitlinger, Markus
author_facet van Os, Wisse
Zeitlinger, Markus
author_sort van Os, Wisse
collection PubMed
description Antibiotic dosing strategies are generally based on systemic drug concentrations. However, drug concentrations at the infection site drive antimicrobial effect, and efficacy predictions and dosing strategies should be based on these concentrations. We set out to review different translational pharmacokinetic-pharmacodynamic (PK/PD) approaches from a target site perspective. The most common approach involves calculating the probability of attaining animal-derived PK/PD index targets, which link PK parameters to antimicrobial susceptibility measures. This approach is time efficient but ignores some aspects of the shape of the PK profile and inter-species differences in drug clearance and distribution, and provides no information on the PD time-course. Time–kill curves, in contrast, depict bacterial response over time. In vitro dynamic time–kill setups allow for the evaluation of bacterial response to clinical PK profiles, but are not representative of the infection site environment. The translational value of in vivo time–kill experiments, conversely, is limited from a PK perspective. Computational PK/PD models, especially when developed using both in vitro and in vivo data and coupled to target site PK models, can bridge translational gaps in both PK and PD. Ultimately, clinical PK and experimental and computational tools should be combined to tailor antibiotic treatment strategies to the site of infection.
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spelling pubmed-86987082021-12-24 Predicting Antimicrobial Activity at the Target Site: Pharmacokinetic/Pharmacodynamic Indices versus Time–Kill Approaches van Os, Wisse Zeitlinger, Markus Antibiotics (Basel) Review Antibiotic dosing strategies are generally based on systemic drug concentrations. However, drug concentrations at the infection site drive antimicrobial effect, and efficacy predictions and dosing strategies should be based on these concentrations. We set out to review different translational pharmacokinetic-pharmacodynamic (PK/PD) approaches from a target site perspective. The most common approach involves calculating the probability of attaining animal-derived PK/PD index targets, which link PK parameters to antimicrobial susceptibility measures. This approach is time efficient but ignores some aspects of the shape of the PK profile and inter-species differences in drug clearance and distribution, and provides no information on the PD time-course. Time–kill curves, in contrast, depict bacterial response over time. In vitro dynamic time–kill setups allow for the evaluation of bacterial response to clinical PK profiles, but are not representative of the infection site environment. The translational value of in vivo time–kill experiments, conversely, is limited from a PK perspective. Computational PK/PD models, especially when developed using both in vitro and in vivo data and coupled to target site PK models, can bridge translational gaps in both PK and PD. Ultimately, clinical PK and experimental and computational tools should be combined to tailor antibiotic treatment strategies to the site of infection. MDPI 2021-12-04 /pmc/articles/PMC8698708/ /pubmed/34943697 http://dx.doi.org/10.3390/antibiotics10121485 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Review
van Os, Wisse
Zeitlinger, Markus
Predicting Antimicrobial Activity at the Target Site: Pharmacokinetic/Pharmacodynamic Indices versus Time–Kill Approaches
title Predicting Antimicrobial Activity at the Target Site: Pharmacokinetic/Pharmacodynamic Indices versus Time–Kill Approaches
title_full Predicting Antimicrobial Activity at the Target Site: Pharmacokinetic/Pharmacodynamic Indices versus Time–Kill Approaches
title_fullStr Predicting Antimicrobial Activity at the Target Site: Pharmacokinetic/Pharmacodynamic Indices versus Time–Kill Approaches
title_full_unstemmed Predicting Antimicrobial Activity at the Target Site: Pharmacokinetic/Pharmacodynamic Indices versus Time–Kill Approaches
title_short Predicting Antimicrobial Activity at the Target Site: Pharmacokinetic/Pharmacodynamic Indices versus Time–Kill Approaches
title_sort predicting antimicrobial activity at the target site: pharmacokinetic/pharmacodynamic indices versus time–kill approaches
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8698708/
https://www.ncbi.nlm.nih.gov/pubmed/34943697
http://dx.doi.org/10.3390/antibiotics10121485
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