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Population Pharmacokinetic Modeling as a Tool To Characterize the Decrease in Ciprofloxacin Free Interstitial Levels Caused by Pseudomonas aeruginosa Biofilm Lung Infection in Wistar Rats
Univ Fed Rio Grande do Sul, Coll Pharm, Pharmaceut Sci Grad Program, Porto Alegre, RS, Brazil..
Univ Fed Rio Grande do Sul, Coll Pharm, Pharmaceut Sci Grad Program, Porto Alegre, RS, Brazil..
Univ Fed Rio Grande do Sul, Coll Pharm, Pharmaceut Sci Grad Program, Porto Alegre, RS, Brazil..
Univ Fed Rio Grande do Sul, Coll Pharm, Pharmaceut Sci Grad Program, Porto Alegre, RS, Brazil.;Univ Fed Rio Grande do Sul, Ctr Biotecnol, Porto Alegre, RS, Brazil..
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2017 (English)In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 61, no 7, article id e02553-16Article in journal (Refereed) Published
Abstract [en]

Biofilm formation plays an important role in the persistence of pulmonary infections, for example, in cystic fibrosis patients. So far, little is known about the antimicrobial lung disposition in biofilm-associated pneumonia. This study aimed to evaluate, by microdialysis, ciprofloxacin (CIP) penetration into the lungs of healthy and Pseudomonas aeruginosa biofilm-infected rats and to develop a comprehensive model to describe the CIP disposition under both conditions. P. aeruginosa was immobilized into alginate beads and intratracheally inoculated 14 days before CIP administration (20 mg/kg of body weight). Plasma and microdialysate were sampled from different animal groups, and the observations were evaluated by noncompartmental analysis (NCA) and population pharmacokinetic (popPK) analysis. The final model that successfully described all data consisted of an arterial and a venous central compartment and two peripheral distribution compartments, and the disposition in the lung was modeled as a two-compartment model structure linked to the venous compartment. Plasma clearance was approximately 32% lower in infected animals, leading to a significantly higher level of plasma CIP exposure (area under the concentration-time curve from time zero to infinity, 27.3 +/- 12.1 mu g . h/ml and 13.3 +/- 3.5 mu g . h/ml in infected and healthy rats, respectively). Despite the plasma exposure, infected animals showed a four times lower tissue concentration/plasma concentration ratio (lung penetration factor = 0.44 and 1.69 in infected and healthy rats, respectively), and lung clearance (CLlung) was added to the model for these animals (CLlung = 0.643 liters/h/kg) to explain the lower tissue concentrations. Our results indicate that P. aeruginosa biofilm infection reduces the CIP free interstitial lung concentrations and increases plasma exposure, suggesting that plasma concentrations alone are not a good surrogate of lung concentrations.

Place, publisher, year, edition, pages
2017. Vol. 61, no 7, article id e02553-16
Keyword [en]
biofilm, Pseudomonas aeruginosa, ciprofloxacin, microdialysis, pneumonia, population pharmacokinetics
National Category
Pharmaceutical Sciences Microbiology in the medical area
Identifiers
URN: urn:nbn:se:uu:diva-333528DOI: 10.1128/AAC.02553-16ISI: 000406257600074OAI: oai:DiVA.org:uu-333528DiVA, id: diva2:1157286
Available from: 2017-11-15 Created: 2017-11-15 Last updated: 2018-01-13Bibliographically approved

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Nielsen, Elisabet I.Friberg, Lena E.

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