title: Semimechanistic pharmacokinetic-pharmacodynamic model with adaptation development for time-kill experiments of ciprofloxacin against Pseudomonas aeruginosa.
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.
authors.affiliation: Université de Poitiers, CHU Poitiers, INSERM Eri-23, Poitiers, France2 France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Grégoire
authors.forename: Sophie
authors.initials: S
authors.lastname: Raherison
authors.forename: Claire
authors.initials: C
authors.lastname: Grignon
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Comets
authors.forename: Manuella
authors.initials: M
authors.lastname: Marliat
authors.forename: Marie-Cécile
authors.initials: MC
authors.lastname: Ploy
authors.forename: William
authors.initials: W
authors.lastname: Couet
mesh_terms: D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D001425:Bacterial Outer Membrane Proteins / Q000235:genetics / Q000378:metabolism; D002939:Ciprofloxacin / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D015169:Colony Count, Microbial; D003428:Cross Infection / Q000188:drug therapy / Q000382:microbiology; D004151:Dipeptides / Q000378:metabolism; D024881:Drug Resistance, Bacterial / Q000235:genetics; D005798:Genes, Bacterial; D006801:Humans; D066298:In Vitro Techniques; D008826:Microbial Sensitivity Tests; D008954:Models, Biological; D009154:Mutation; D011552:Pseudomonas Infections / Q000188:drug therapy / Q000382:microbiology; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D001425:Bacterial Outer Membrane Proteins; D004151:Dipeptides; C105708:OprN protein, Pseudomonas aeruginosa; C419365:phenylalanine arginine beta-naphthylamide; D002939:Ciprofloxacin