Population pharmacokinetic modeling of the influence of chronic and acute biofilm-forming Pseudomonas aeruginosa lung infection on ciprofloxacin free pulmonary and epithelial lining fluid concentrations

Abstract

We previously reported that ciprofloxacin (CIP) free lung interstitial concentrations are decreased by biofilm-forming Pseudomonas aeruginosa pulmonary chronic (14 d) infection. To get a better understanding on the influence of infection on CIP lung distribution, in the present study free lung interstitial fluid and epithelial lining fluid (ELF) concentrations were determined by microdialysis in biofilm-forming P. aeruginosa acutely (2 d) and chronically infected (14 d) Wistar rats following CIP 20 mg/kg i.v. bolus dosing. A popPK model was developed, using NONMEM® (version 7.4.3) with FOCE+I, with plasma data described as a three-compartment model with first-order elimination. For lung data inclusion, the model was expanded to four compartments and ELF concentrations were described as a fraction of lung levels estimated as a distribution factor (ƒD). Acute infection had a minor impact on plasma and lung CIP distribution and both infection stages did not alter ELF drug penetration. Probability of target attainment of ƒAUC0–24/MIC ≥ 90 using 20 mg q8h, equivalent to 400 mg q8h in humans, showed that CIP free concentrations in plasma are adequate to successfully treat lung infections. However, lung and ELF free interstitial concentrations might be insufficient to result in efficacious treatment of biofilm-forming P. aeruginosa chronic infection. However, lung and ELF free interstitial concentrations might be insufficient to result in efficacious treatment of biofilm-forming P. aeruginosa chronic infection.