Curriculum Vitae

Quantitative pharmacokinetic/pharmacodynamic understanding of the antibiotic combination therapy of piperacillin and tazobactam against Escherichia coli

- combining in vitro and in silico approaches to potentially improve clinical outcomes and to suppress antibiotic resistance

Antimicrobial resistance was listed on “Ten threats to global health in 2019” by the World Health Organization [1]. One way to tackle this threat would be to optimize the efficacy of available antibacterial therapies, such as piperacillin/tazobactam (PIP/TAZ). PIP/TAZ is a widely used antibacterial combination therapy and is a recommended first line option for empirical therapy for intra-abdominal infections, urinary tract infections/uncomplicated pyelonephritis, lower respiratory infections, and sepsis in Germany [2]. While PIP is a ß-lactam antibiotic responsible for the bactericidal effect, TAZ acts as a ß‑lactamases inhibitor, extending PIP bactericidal effect by deactivating bacterial ß‑lactamase. PIP/TAZ has in recent years gained an increased interest due to TAZ effectiveness of inhibiting extended spectrum ß-lactamases (ESBL) belonging to the group of CTX-M [3]. This would make the combination a valuable option against the spread of ESBL-producing Gram-negative pathogens, and a promising alternative to carbapenems, another type of ß-lactam antibiotic, that long has been the first line therapeutic option against ESBL producing‑Enterobacteriaceae.

PIP/TAZ is today administrated in a fixed 8:1 dose ratio and the minimum inhibitory concentration (MIC) of the combination is determined using a fixed TAZ concentration of 4 mg/L [4, 5]. However, the rationale underlying the fixed TAZ concentration is not specified nor is how the resulting MIC is related to the 8:1 dose ratio used in vivo. Essential for finding a rationale dosing strategy for a drug is the quantitative understanding of the pharmacokinetics (PK) and the pharmacodynamics (PD) of the drug and the relationship between the two. How the PK of the combination is related to the PD and vice versa highlights the need for further investigations. Therefore, this project aims to elucidate the mechanistic PK/PD relationship of PIP/TAZ against E. coli isolates towards optimised dosing strategies to potentially improve clinical outcomes and to suppress antibiotic resistance.

The core of this project will be to perform in vitro experiments investigating different PIP/TAZ concentration combinations to assess the concentration and time dependence of the PK/PD. In addition, a mechanistic PD model describing the PD interaction between the drugs as well as the drug‑pathogen interaction will be developed in silico. The mechanistic model will be enable to describe the dynamics in the system, including resistance development. Furthermore, a new PD metric shall be derived that includes the consideration of TAZ enhancing effect of PIP bactericidal effect and resistance evolution. For antibiotics, the MIC is often used as a PD metric and in conjunction with the PK to derive PK/PD indices that are related to e.g., treatment outcome. However, the MIC is a summary metric with the limitation of being based on a single time point visual read out and does not accurately reflect kill or (re)-growth dynamics. Moving beyond the MIC, a quantitative mechanistic understanding of the PK/PD of PIP/TAZ and resistance development would enable to apply a translational approach facilitating the design of optimised dosing regimens.

References

[1] World Health Organization. Ten Threats to Global Health in 2019. (2019)
[2] Paul-Ehrlich-Gesellschaft für Infektionstherapie. S2k-Leitlinie Kalkulierte parenterale Initialtherapie bakterieller Erkrankungen bei Erwachsenen (2022).
[3] Monogue et al., Pharmacotherapy. (2021).
[4] Pfizer Inc. Tazocin® - Summary of product characteristics (2014).
[5] EUCAST. Breakpoint tables for interpretation of MICs and zone diameters. (2022).