1. Semimechanistic Pharmacokinetic-Pharmacodynamic Model with Adaptation Development for Time-Kill Experiments of Ciprofloxacin against Pseudomonas aeruginosa
- Author
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Nicolas Grégoire, Emmanuelle Comets, William Couet, Marie-Cécile Ploy, Manuella Marliat, Sophie Raherison, Claire Grignon, Modélisations pharmacocinétiques-pharmacodynamiques pour un meilleur usage des anti-infectieux, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Poitiers, Centre hospitalier universitaire de Poitiers (CHU Poitiers), Biologie moléculaire et cellulaire des microorganismes (EA3175), Université de Limoges (UNILIM)-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503)-Institut National de la Santé et de la Recherche Médicale (INSERM), Modèles et méthodes de l'évaluation thérapeutique des maladies chroniques (U738 / UMR_S738), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7), Université de Poitiers-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Raherison, Sophie
- Subjects
Antibiotics ,Colony Count, Microbial ,Drug resistance ,Pharmacology ,medicine.disease_cause ,030226 pharmacology & pharmacy ,0302 clinical medicine ,MESH: Dipeptides ,Ciprofloxacin ,[SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases ,Pharmacology (medical) ,[SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology ,Cross Infection ,MESH: Microbial Sensitivity Tests ,0303 health sciences ,education.field_of_study ,MESH: Pseudomonas Infections ,Dipeptides ,Anti-Bacterial Agents ,Infectious Diseases ,Pseudomonas aeruginosa ,MESH: Pseudomonas aeruginosa ,[SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology ,[SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases ,Efflux ,MESH: Genes, Bacterial ,Bacterial Outer Membrane Proteins ,medicine.drug ,MESH: Mutation ,medicine.drug_class ,Population ,Microbial Sensitivity Tests ,In Vitro Techniques ,Biology ,Models, Biological ,Microbiology ,03 medical and health sciences ,Pharmacokinetics ,In vivo ,MESH: Anti-Bacterial Agents ,Drug Resistance, Bacterial ,MESH: Drug Resistance, Bacterial ,medicine ,Humans ,Experimental Therapeutics ,Pseudomonas Infections ,MESH: Ciprofloxacin ,education ,MESH: Colony Count, Microbial ,MESH: Humans ,030306 microbiology ,MESH: Bacterial Outer Membrane Proteins ,MESH: Models, Biological ,MESH: Cross Infection ,[SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology ,Genes, Bacterial ,Mutation ,[SDV.MP.BAC] Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology - Abstract
The objective of this study was to implement a semimechanistic pharmacokinetic-pharmacodynamic (PK-PD) model to describe the effects of ciprofloxacin against Pseudomonas aeruginosa in vitro. Time-kill curves were generated with an initial inoculum close to 5 × 10 6 CFU/ml of P. aeruginosa PAO1 and constant ciprofloxacin concentrations between 0.12 and 4.0 μg/ml (corresponding to 0.5× and 16× MIC). To support the model, phenotypic experiments were conducted with the PAO7H mutant strain, which overexpresses the MexEF OprN efflux pump and phenyl arginine β-naphthylamide (PAβN), a known efflux inhibitor of main Mex multidrug efflux systems. A population approach was used for parameter estimation. At subinhibitory ciprofloxacin concentrations (0.12 and 0.25 μg/ml), an initial CFU decay followed by regrowth was observed, attesting to rapid emergence of bacteria with increased but moderate resistance (8-fold increase of MIC). This phenomenon was mainly due to an overexpression of the Mex protein efflux pumps, as shown by a 16-fold diminution of the MIC in the presence of PAβN in these strains with low-level resistance. A PK-PD model with adaptation development was successfully used to describe these data. However, additional experiments are required to validate the robustness of this model after longer exposure periods and multiple dosing regimens, as well as in vivo.
- Published
- 2010