title: 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.
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 microg/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 microg/ml; half-life [t(1/2)], 10 h; free-drug C(max) in ELF, 6.0 microg/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 microg/ml, area under the curve to MIC (AUC(0-24 h)) 6.4 +/- 1.5 microg . 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 microg/ml, AUC(0-24 h) 45.5 +/- 5.5 microg . 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 microg/ml and 1 microg/ml, respectively. Free-telithromycin S and ELF concentrations simulating C(max)/MIC > or = 3.5 and AUC(0-24 h)/MIC > or = 25 completely eradicated (> or =4 log(10) killing) macrolide-resistant S. pneumoniae at 24 and 48 h. Free-telithromycin concentrations in serum simulating C(max)/MIC > or = 1.8 and AUC(0-24 h)/MIC > or = 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 > or = 3.5 and AUC(0-24 h)/MIC > or = 25 completely eradicated (> or =4 log(10) killing) macrolide-resistant S. pneumoniae at 24 and 48 h.
authors.affiliation: Department of Medical Microbiology, University of Manitoba, Winnipeg, Manitoba, Canada. ggzhanel@pcs.mb.ca
authors.forename: George G
authors.initials: GG
authors.lastname: Zhanel
authors.forename: Christel
authors.initials: C
authors.lastname: Johanson
authors.forename: Nancy
authors.initials: N
authors.lastname: Laing
authors.forename: Tamiko
authors.initials: T
authors.lastname: Hisanaga
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Wierzbowski
authors.forename: Daryl J
authors.initials: DJ
authors.lastname: Hoban
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D019540:Area Under Curve; D001426:Bacterial Proteins / Q000378:metabolism*; D001826:Body Fluids / Q000378:metabolism; D003198:Computer Simulation; D024881:Drug Resistance, Bacterial; D004848:Epithelium / Q000378:metabolism; D006207:Half-Life; D048628:Ketolides / Q000097:blood / Q000494:pharmacology*; D018942:Macrolides / Q000494:pharmacology*; D008565:Membrane Proteins / Q000378:metabolism*; D008826:Microbial Sensitivity Tests; D013296:Streptococcus pneumoniae / Q000187:drug effects*
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D048628:Ketolides; D018942:Macrolides; C431304:MefE protein, Streptococcus pneumoniae; D008565:Membrane Proteins; C106791:telithromycin