Penetration, efflux and intracellular activity of tigecycline in human polymorphonuclear neutrophils (PMNs)
Christine T Ong1, Chinedum P Babalola, Charles H Nightingale
1Center for Anti-Infective Research and Development, Hartford Hospital, 80 Seymour Street, Hartford, CT 06102, USA.
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 x 10(6) cells/mL at 37 degrees 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 approximately 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.
Insights
Tigecycline rapidly enters human polymorphonuclear neutrophils (PMNs), reaching high intracellular concentrations. This antibiotic demonstrated static activity against Staphylococcus aureus within PMNs, suggesting clinical utility.
Area of Science:
- Pharmacology
- Immunology
- Microbiology
Background:
- Polymorphonuclear neutrophils (PMNs) are critical immune cells involved in combating bacterial infections.
- Understanding intracellular antibiotic activity is crucial for effective treatment of intracellular pathogens.
Purpose of the Study:
- To assess the penetration, efflux, and intracellular antimicrobial activity of tigecycline within human PMNs.
- To evaluate tigecycline's efficacy against Staphylococcus aureus residing inside PMNs.
Main Methods:
- Human PMNs were isolated and incubated with varying concentrations of tigecycline (1-10 mg/L) for up to 3 hours.
- Drug uptake, efflux kinetics (half-life), and intracellular activity against S. aureus were measured.
Main Results:
- Tigecycline demonstrated rapid penetration into PMNs, achieving concentrations significantly higher (20-30 times) than extracellular levels within 1 hour.
- Intracellular drug levels remained high for 3 hours, with an efflux half-life of 1.39 hours.
- Tigecycline exhibited bacteriostatic activity against intracellular S. aureus.
Conclusions:
- Tigecycline achieves substantial intracellular concentrations in human PMNs.
- The drug's intracellular bacteriostatic effect against S. aureus supports its potential clinical application in treating infections involving these cells.
