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

Abstract

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.

Integration of individual preclinical and clinical anti‐infective PKPD data to predict clinical study outcomes

“…Indeed, the developed workflow could be applied to other drugs, bacteria, and sources of in vitro and/or in vivo data that can be linked with bacterial density predictions through semi‐mechanistic PKPD models. For example, predictions from PK models describing the unbound concentrations at the site of action may provide a more precise link to outcome, 29 and ideally the impact of the immune system on the infecting pathogen could be considered 30 . Future research should focus on the contribution of host‐related factors to bacterial killing and clinical outcomes, as this will also enhance our understanding of the relative contributions of drug and pathogen‐related factors 31 …”

Pharmacokinetics and Pharmacodynamics (PK/PD) of Corallopyronin A against Methicillin-Resistant Staphylococcus aureus

“…Moreover, information about measured tissue and plasma concentrations as well as the PD effect fed into in silico models might help to understand PK/PD drivers in a better way. As tissues can be represented with their compartmental (sub-)structures in in silico models, this allows to calculate the PD effect in specific target tissues [ 37 , 38 ]. A first rough estimation of human equivalent doses using the concept of Reagan-Shaw and colleagues [ 39 ] based on the efficacy data from this study shows that 100 mg/kg would be equivalent to 8.1 mg/kg human dose, whereas a dose of 60 mg/kg has a human equivalent dose of 4.9 mg/kg.…”

Translational PK/PD for the Development of Novel Antibiotics—A Drug Developer’s Perspective

“…Several reviews discussing the limitations of the PK/PD index approach have already been published [66][67][68][69], and semi-mechanistic PK/PD modeling is often suggested as an alternative to overcome the limitations of the MIC-based PK/PD index approach. However, from a drug developer's perspective, a complete transition from the PK/PD index approach to the semi-mechanistic PK/PD modeling may pose challenges or may not be entirely suitable.…”