Semimechanistic pharmacokinetic-pharmacodynamic model with adaptation development for time-kill experiments of ciprofloxacin against Pseudomonas aeruginosa

Nicolas Grégoire 1, 2 Sophie Raherison 3 Claire Grignon 1, 2 Emmanuelle Comets 4 Manuella Marliat 1, 2 Marie-Cécile Ploy 3 William Couet 1, 2
1 Pharmacologie des anti-infectieux
2 CHU Poitiers - Centre hospitalier universitaire de Poitiers
3 EA3175 - Biologie moléculaire et cellulaire des microorganismes
4 Modèles et méthodes de l'évaluation thérapeutique des maladies chroniques
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 x 10(6)CFU/ml of P. aeruginosa PAO1 and constant ciprofloxacin concentrations between 0.12 and 4.0 microg/ml (corresponding to 0.5x and 16x MIC). To support the model, phenotypic experiments were conducted with the PAO7H mutant strain, which overexpresses the MexEF OprN efflux pump and phenyl arginine beta-naphthylamide (PAbetaN), 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 microg/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 PAbetaN 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.
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Article dans une revue
Antimicrobial Agents and Chemotherapy, American Society for Microbiology, 2010, 54 (6), pp.2379-2384. 〈10.1128/AAC.01478-08〉
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http://www.hal.inserm.fr/inserm-00533219
Contributeur : Sophie Raherison <>
Soumis le : vendredi 5 novembre 2010 - 14:57:26
Dernière modification le : mercredi 5 septembre 2018 - 13:30:06

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UNIV-POITIERS | UNILIM | UMR-S1092 | GEIST | USPC

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Nicolas Grégoire, Sophie Raherison, Claire Grignon, Emmanuelle Comets, Manuella Marliat, et al.. Semimechanistic pharmacokinetic-pharmacodynamic model with adaptation development for time-kill experiments of ciprofloxacin against Pseudomonas aeruginosa. Antimicrobial Agents and Chemotherapy, American Society for Microbiology, 2010, 54 (6), pp.2379-2384. 〈10.1128/AAC.01478-08〉. 〈inserm-00533219〉

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