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.

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 mu g/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 mu g/ml; half-life [t(1/2)], 10 h; free-drug C-max in ELF, 6.0 mu g/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 mu g/ml, area under the curve to MIC (AUC(0-24) h) 6.4 +/- 1.5 mu g (.) 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 mu g/ml, AUC(0-24) (h) 45.5 +/- 5.5 mu g (.) 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 mu g/ml and 1 mu g/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.