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Combination of β-lactam Aztreonam and β-lactamase Inhibitor Avibactam: Differences between Predictions from a Semi-Mechanistic PKPD-Model based on Static Time-Kill Studies and Data from a Hollow Fiber Infection Model (HFIM)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
2018 (English)Independent thesis Advanced level (degree of Master (One Year)), 20 credits / 30 HE creditsStudent thesis
Abstract [en]

Introduction: The β-lactam antibiotic aztreonam (ATM) interfere with the cell wall synthesis of Gram-negative bacteria to induce cell death. Bacteria become resistant by producing β-lactamases. Avibactam (AVI), a β-lactamase inhibitor, can protect ATM from degradation due to β-lactamases. An ongoing project at the INSERM Unit of Pharmacology of Antimicrobial Agents in Poitiers, France, aims to investigate the pharmacokinetic and pharmacodynamic (PKPD) features of ATM/AVI on 4 strains of enterobacteria using a semi-mechanistic PKPD model based on static time-kill studies. The intention is to validate the model with a hollow fiber infection model (HFIM). HFIM is a dynamic in vitro model mimicking the drug half-life that can be used to study different posologies to find a suitable dosing regimen. The first HFIM trials show a bacterial killing distinctly faster than predicted  and can not be used as validation.

Aim: To explain the faster bacterial killing in HFIM. Several theories are examined.

Methods: Comparing model simulations with static and dynamic HFIM experiments, to find an intrinsic feature of the HFIM system that could explain the differences in bacterial behaviour.

Results: It seems like a high flow from the central compartment to the cartridge could increase the bacterial killing. This could be due to a high input of nutrients, a high antibiotic exposure and by β-lactamases or bacterial signal substances being “washed” out of the cartridge.

Conclusion: When using HFIM as a validation method, it is important to be aware of factors that can affect the bacterial behaviour in the model. For bacterial strains producing β-lactamses this is particulary important. Eventhough, the HFIM could still be useful for simulating different posologies.

Place, publisher, year, edition, pages
2018. , p. 30
Keywords [en]
Aztreonam, avibactam, hollow fiber infection model, semi-mechanistic PKPD-model
National Category
Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-355257OAI: oai:DiVA.org:uu-355257DiVA, id: diva2:1228194
External cooperation
INSERM Unit 1070 Poitiers France
Subject / course
Pharmacokinetics
Educational program
Master of Science Programme in Pharmacy
Presentation
2018-05-28, B7:111BMC, Husargatan 3 75124, Uppsala, 17:01 (English)
Supervisors
Examiners
Available from: 2018-06-28 Created: 2018-06-27 Last updated: 2018-06-28Bibliographically approved

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