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

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Abstract
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 10 6 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 log 10 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 log 10 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 log 10 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 log 10 killing) macrolide-resistant S. pneumoniae at 24 and 48 h.

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