Pharmacokinetic and Pharmacodynamic Efficacy of Intrapulmonary Administration of Ciprofloxacin for the Treatment of Respiratory Infections

Abstract

The pharmacokinetic and pharmacodynamic efficacy of intrapulmonary administration of ciprofloxacin (CPFX) for the treatment of respiratory infections caused by pathogenic microorganisms resisting sterilization systems of alveolar macrophages (AMs) was evaluated by comparison with an oral administration. The time-courses of the concentration of CPFX in AMs and lung epithelial lining fluid (ELF) following intrapulmonary administration of CPFX solution to rats (200 microg/kg) were markedly higher than that following oral administration (10 mg/kg). The time-course of the concentrations of CPFX in plasma following intrapulmonary administration was markedly lower than that in AMs and ELF. These results indicate that intrapulmonary administration is more effective in delivering CPFX to AMs and ELF, compared with oral administration, in spite of a low dose and it avoids distribution of CPFX to the blood. In addition, the antibacterial effects of CPFX in AMs and ELF following intrapulmonary administration were evaluated by pharmacokinetics/pharmacodynamics analysis. The concentration of CPFX in AMs and ELF-time curve (AUC)/minimum inhibitory concentration of CPFX (MIC) ratio and the maximum concentration of CPFX in AMs and ELF (Cmax)/MIC ratio were markedly higher than the effective values. The present study indicates that intrapulmonary administration of CPFX is an effective technique for the treatment of respiratory infections.

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“…Administration of 200 μ g/kg of ciprofloxacin can reach 40 and 20 μ g/ml values in alveolar macrophages and epithelial lining fluid, respectively. This method allows administration of lower doses of ciprofloxacin compared to the oral route (23). LC50 after 48 h (100 μ g/ml) can be theoretically achieved in vivo in lung tissue (Table I).…”

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“…Finally, the k nad value for CPFX (0.61 h −1 ) was equivalent to the rate constant of mucociliary clearance (0.4–0.7 h −1 ; Byron, ). No local lung degradation or tissue binding/sequestration was found, and alveolar macrophagic phagocytosis was certain but essentially of no impact on the lung disposition kinetics and systemic PK profiles following lung delivery in rats (Chono, Tanino, Seki, & Morimoto, ; Cipolla, Blanchard, & Gonda, ). Hence, mucociliary clearance was considered to be the primary non‐absorptive disposition mechanism for CPFX in the lung.…”

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“…Chono and colleagues [133] investigated the potential efficacy of intratracheal-delivered ciprofloxacin by calculating the ratio of lung drug levels as quantified in a PK study in rats to the MICs of a suite of intracellular and extracellular pathogens. The Cmax/MIC ratio was far higher following intrapulmonary delivery of ciprofloxacin solution compared to oral administration.…”

“…In comparison with systemic administration, pulmonary delivery of ciprofloxacin has been demonstrated to achieve higher local lung concentrations. A pre-clinical study comparing the PK of ciprofloxacin delivered via intratracheal dosing (200 µg/kg) and through oral administration (10 mg/kg) [133] found clear increases in drug ELF concentrations following intrapulmonary delivery compared to oral. ELF Cmax was determined to be 17.6 ±1.4µg/mL following IT vs 0.15 ±0.02 µg/mL following oral administration, despite the far higher dose used in oral delivery.…”