Penetration, efflux and intracellular activity of tigecycline in human polymorphonuclear neutrophils (PMNs)

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Abstract
Objectives: To evaluate the penetration, efflux and intracellular activity of tigecycline in human polymorphonuclear neutrophils (PMNs). Methods: PMNs were isolated from fresh whole blood and tested for viability and purity prior to use. Tigecycline drug uptake was evaluated by incubating 5 × 106 cells/mL at 37°C up to 3 h at tigecycline concentrations of 1, 2, 5 and 10 mg/L. Drug efflux from PMNs was determined following a 2 h incubation with tigecycline at 10 mg/L. Its intracellular activity against Staphylococcus aureus was evaluated following tigecycline extracellular exposures of 1 mg/L. Results: Tigecycline uptake was rapid and achieved high concentrations within PMNs with maximal penetration noted at 1 h of incubation. At 1 h, dose-dependent intracellular concentrations ranged from 15.83 ± 11.09 mg/L to 264 ± 54.60 mg/L at tigecycline 1 and 10 mg/L, respectively. At these exposures, intracellular drug concentrations were ∼20 and 30 times higher at 1 h than extracellular concentrations. By 3 h, tigecycline displayed sustained high intracellular exposures. Tigecycline cell efflux followed first order kinetics with a half-life of 1.39 h. Tigecycline was bacteriostatic against intracellular S. aureus. Conclusions: Tigecycline rapidly achieved high intracellular concentrations in PMNs and exhibited static activity against S. aureus supporting its potential clinical utilization.

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