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Antimicrobial Agents and Chemotherapy, May 2005, p. 1943-1948, Vol. 49, No. 5
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.5.1943-1948.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Pharmacodynamic Activity of Telithromycin at Simulated Clinically Achievable Free-Drug Concentrations in Serum and Epithelial Lining Fluid against Efflux (mefE)-Producing Macrolide- Resistant Streptococcus pneumoniae for Which Telithromycin MICs Vary

Department of Medical Microbiology, Faculty of Medicine, University of Manitoba, and Departments of Clinical,¹ Microbiology,² Medicine, Health Sciences Centre, Winnipeg, Manitoba, Canada³

Received 20 October 2004/ Returned for modification 6 December 2004/ Accepted 19 January 2005

The present study, using an in vitro model, assessed telithromycin pharmacodynamic activity at simulated clinically achievable free-drug concentrations in serum (S) and epithelial lining fluid (ELF) against efflux (mefE)-producing macrolide-resistant Streptococcus pneumoniae. Two macrolide-susceptible (PCR negative for both mefE and ermB) and 11 efflux-producing macrolide-resistant [PCR-positive for mefE and negative for ermB) S. pneumoniae strains with various telithromycin MICs (0.015 to 1 µg/ml) were tested. The steady-state pharmacokinetics of telithromycin were modeled, simulating a dosage of 800 mg orally once daily administered at time 0 and at 24 h (free-drug maximum concentration [C_max] in serum, 0.7 µg/ml; half-life [t_1/2], 10 h; free-drug C_max in ELF, 6.0 µg/ml; t_1/2, 10 h). Starting inocula were 10⁶ CFU/ml in Mueller-Hinton Broth with 2% lysed horse blood. Sampling at 0, 2, 4, 6, 12, 24, and 48 h assessed the extent of bacterial killing (decrease in log₁₀ CFU/ml versus initial inoculum). Free-telithromycin concentrations in serum achieved in the model were C_max 0.9 ± 0.08 µg/ml, area under the curve to MIC (AUC_{0-24 h}) 6.4 ± 1.5 µg · h/ml, and t_1/2 of 10.6 ± 0.6 h. Telithromycin-free ELF concentrations achieved in the model were C_max 6.6 ± 0.8 µg/ml, AUC_{0-24 h} 45.5 ± 5.5 µg · h/ml, and t_1/2 of 10.5 ± 1.7 h. Free-telithromycin S and ELF concentrations rapidly eradicated efflux-producing macrolide-resistant S. pneumoniae with telithromycin MICs up to and including 0.25 µg/ml and 1 µg/ml, respectively. Free-telithromycin S and ELF concentrations simulating C_max/MIC 3.5 and AUC_{0-24 h}/MIC 25 completely eradicated (4 log₁₀ killing) macrolide-resistant S. pneumoniae at 24 and 48 h. Free-telithromycin concentrations in serum simulating C_max/MIC 1.8 and AUC_{0-24 h}/MIC 12.5 were bacteriostatic (0.1 to 0.2 log₁₀ killing) against macrolide-resistant S. pneumoniae at 24 and 48 h. In conclusion, free-telithromycin concentrations in serum and ELF simulating C_max/MIC 3.5 and AUC_{0-24 h}/MIC 25 completely eradicated (4 log₁₀ killing) macrolide-resistant S. pneumoniae at 24 and 48 h.