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JAC Advance Access published online on July 15, 2005
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dki260
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© The Author 2005. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oupjournals.org
Received November 22, 2004
Revised June 21, 2005
Accepted June 25, 2005

Original article

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

Christine T. Ong 1, Chinedum P. Babalola 1, Charles H. Nightingale 1, and David P. Nicolau 2*

1 Center for Anti-Infective Research and Development, Hartford Hospital, 80 Seymour Street, Hartford, CT 06102, USA
2 Center for Anti-Infective Research and Development, Hartford Hospital, 80 Seymour Street, Hartford, CT 06102, USA; Division of Infectious Diseases, Hartford Hospital, Hartford, CT 06102, USA

* To whom correspondence should be addressed.
David P. Nicolau, E-mail: dnicola{at}harthosp.org


  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 x 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.

Keywords: glycylcyclines; intracellular concentration; phagocytes.
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