| Semimechanistic pharmacokinetic-pharmacodynamic model with adaptation development for time-kill experiments of ciprofloxacin against Pseudomonas aeruginosa. | |
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MedLine Citation:
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PMID: 20368392 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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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Authors:
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Nicolas Grégoire; Sophie Raherison; Claire Grignon; Emmanuelle Comets; Manuella Marliat; Marie-Cécile Ploy; William Couet |
Publication Detail:
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Type: In Vitro; Journal Article Date: 2010-04-05 |
Journal Detail:
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Title: Antimicrobial agents and chemotherapy Volume: 54 ISSN: 1098-6596 ISO Abbreviation: Antimicrob. Agents Chemother. Publication Date: 2010 Jun |
Date Detail:
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Created Date: 2010-05-18 Completed Date: 2010-09-14 Revised Date: 2011-03-03 |
Medline Journal Info:
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Nlm Unique ID: 0315061 Medline TA: Antimicrob Agents Chemother Country: United States |
Other Details:
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Languages: eng Pagination: 2379-84 Citation Subset: IM |
Affiliation:
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Université de Poitiers, CHU Poitiers, INSERM Eri-23, Poitiers, France2 France. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Anti-Bacterial Agents
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administration & dosage,
pharmacokinetics*,
pharmacology* Bacterial Outer Membrane Proteins / genetics, metabolism Ciprofloxacin / administration & dosage, pharmacokinetics*, pharmacology* Colony Count, Microbial Cross Infection / drug therapy, microbiology Dipeptides / metabolism Drug Resistance, Bacterial / genetics Genes, Bacterial Humans Microbial Sensitivity Tests Models, Biological Mutation Pseudomonas Infections / drug therapy, microbiology Pseudomonas aeruginosa / drug effects*, genetics, metabolism |
| Chemical | |
Reg. No./Substance:
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0/Anti-Bacterial Agents; 0/Bacterial Outer Membrane Proteins; 0/Dipeptides; 0/OprN protein, Pseudomonas aeruginosa; 0/phenylalanine arginine beta-naphthylamide; 85721-33-1/Ciprofloxacin |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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