An integrated pharmacokinetic, pharmacogenomic and pharmacodynamic study of fluoroquinolones in the context of intracellular infections
(2025)
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- Staphylococcus aureus infections pose a major health challenge, especially with methicillin-resistant strains and their ability to persist intracellularly, limiting antibiotic efficacy. Fluoroquinolones (FQs) like moxifloxacin (MXF) and ciprofloxacin (CIP) show promise, but their intracellular efficacy is influenced by ATP-binding cassette (ABC) transporters, the activity of which can be affected by genetic polymorphisms. In vivo fluctuations of drug concentrations may also affect FQ accumulation, compromising their effectiveness. This work investigates the interplay between FQ pharmacokinetics (PK), pharmacodynamics (PD), and pharmacogenomics (PG) by analyzing ABC transporters’ roles and polymorphisms and developing an intracellular PD model simulating clinical drug exposure. We demonstrated that ABCB1 and ABCC4 regulate MXF and CIP transport, with ABCB1 haplotypes reducing FQ efflux. Compared to the static model, the intracellular PD model showed enhanced MXF activity against intracellular S. aureus, while CIP was less effective. This thesis highlights the importance of integrating PK, PD, and PG to assess antibiotic efficacy against intracellular infections.
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MAHIEU, G. (2025). An integrated pharmacokinetic, pharmacogenomic and pharmacodynamic study of fluoroquinolones in the context of intracellular infections. https://hdl.handle.net/2078.5/243593