title: Pharmacodynamic activity of telithromycin against macrolide-susceptible and macrolide-resistant Streptococcus pneumoniae simulating clinically achievable free serum and epithelial lining fluid concentrations.
abstract: BACKGROUND
  The association between macrolide resistance mechanisms and ketolide bacteriological eradication of Streptococcus pneumoniae remains poorly studied. The present study, using an in vitro model, assessed telithromycin pharmacodynamic activity against macrolide-susceptible and macrolide-resistant S. pneumoniae simulating clinically achievable free serum and epithelial lining fluid (ELF) concentrations.
  
  
  METHODS
  Two macrolide-susceptible [PCR-negative for both mef(A) and erm(B)] and six macrolide-resistant [five mef(A)-positive/erm(B)-negative displaying various degrees of macrolide resistance and one mef(A)-negative/erm(B)-positive] S. pneumoniae were tested. Telithromycin was modelled simulating a dosage of 800 mg by mouth once daily [free serum: maximum concentration (C(max)) 0.7 mg/L, t(1/2) 10 h; and free ELF: C(max) 6.0 mg/L, t(1/2) 10 h]. Starting inocula were 1 x 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).
  
  
  RESULTS
  Telithromycin free serum concentrations achieved in the model were: C(max) 0.9+/-0.08 mg/L, AUC(0-24) 6.4+/-1.5 mg.h/L and t(1/2) of 10.6+/-1.6 h. Telithromycin free ELF concentrations achieved in the model were: C(max) 6.6+/-0.8 mg/L, AUC(0-24) 45.5+/-5.5 mg.h/L and t(1/2) of 10.5+/-1.7 h. At 2 h, free serum telithromycin concentrations achieved a 1.0-1.9 log(10) reduction in inoculum compared with a 3.0-3.3 log(10) reduction with free ELF versus macrolide-susceptible and macrolide-resistant S. pneumoniae. Free telithromycin serum and ELF concentrations simulating C(max)/MIC > or =14.1 and area under the curve to MIC (AUC(0-24)/MIC) > or =100 [time above the MIC (t > MIC) of 100%], were bactericidal (> or =3 log(10) killing) at 4, 6, 12, 24 and 48 h versus macrolide-susceptible and macrolide-resistant S. pneumoniae.
  
  
  CONCLUSIONS
  Telithromycin serum and ELF concentrations rapidly eradicated macrolide-susceptible and macrolide-resistant S. pneumoniae regardless of resistance phenotype. Achieving C(max)/MIC > or =14.1 and AUC(0-24)/MIC > or =100 resulted in bactericidal activity at 4 h with no regrowth over 48 h.
authors.affiliation: Department of Medical Microbiology, Faculty of Medicine, University of 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: Tamiko
authors.initials: T
authors.lastname: Hisanaga
authors.forename: Chris
authors.initials: C
authors.lastname: Mendoza
authors.forename: Nancy
authors.initials: N
authors.lastname: Laing
authors.forename: Ayman
authors.initials: A
authors.lastname: Noreddin
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*; D001426:Bacterial Proteins / Q000235:genetics; D001826:Body Fluids / Q000378:metabolism; D015169:Colony Count, Microbial; D003470:Culture Media; D024881:Drug Resistance, Bacterial / Q000235:genetics; D004848:Epithelium / Q000378:metabolism; D006801:Humans; D048628:Ketolides / Q000493:pharmacokinetics* / Q000494:pharmacology*; D018942:Macrolides / Q000493:pharmacokinetics* / Q000494:pharmacology*; D008565:Membrane Proteins / Q000235:genetics; D008826:Microbial Sensitivity Tests / Q000592:standards; D008954:Models, Biological; D013296:Streptococcus pneumoniae / Q000187:drug effects* / Q000254:growth & development
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D003470:Culture Media; D048628:Ketolides; D018942:Macrolides; C117866:MefA protein, Streptococcus; D008565:Membrane Proteins; C106791:telithromycin